- Design, synthesis and diversification of natural product-inspired hydantoin-fused tetrahydroazepino indoles
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A facile and efficient synthesis of novel oxo, thio and seleno hydantoin fused tetrahydroazepino [4,5-b]indoles was reported. A naturally occurring iboga class alkaloid inspired seven-membered azepino[4,5-b]indole ring was synthesized as a new scaffold through Pictet-Spengler reaction followed by skeletal rearrangement of the aziridine ring. To improve the efficiency of the synthetic route, the double bond of the rearranged olefinic product 5 was reduced and a privileged hydantoin moiety was constructed on the core system through urea formation using a variety of isocyanates, isothiocyanates and isoselenocyanates followed by intramolecular cyclization to incorporate elements of diversity. The regeneration of the double bond of intermediate 9 afforded hydantoin-fused tetrahydroazepino [4,5-b]indoles.
- Barve, Indrajeet J.,Dalvi, Prashant B.,Thikekar, Tushar Ulhas,Chanda, Kaushik,Liu, Yu-Li,Fang, Chiu-Ping,Liu, Chia-Chen,Sun, Chung-Ming
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- Design of novel mycobacterium tuberculosis pantothenate synthetase inhibitors: Virtual screening, synthesis and in vitro biological activities
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Pantothenate synthetase (PS) enzyme involved in the pantothenate biosynthetic pathway is essential for the virulence and persistent growth of Mycobacterium tuberculosis (MTB). It is encoded by the panC gene, and has become an appropriate target for developing new therapeutics for tuberculosis. Here we report new inhibitors active against MTB PS developed using energy based pharmacophore modelling of the available protein-inhibitor complex (3IVX) and virtual screening of a large commercial library. The e-pharmacophore model consisted of a ring aromatic (R), negative ionizable (N) and acceptor (A) sites. Compounds 5 and 10 emerged as promising hits with IC50s 2.18 μM and 6.63 μM respectively. Further structural optimization was attempted to optimize lead 10 using medicinal chemistry approach and six compounds were found to exhibit better enzyme inhibition compared to parent compound lead 10 (6 μM).
- Devi, Parthiban Brindha,Jogula, Sridhar,Reddy, Asireddy Parameshwar,Saxena, Shalini,Sridevi, Jonnalagadda Padma,Sriram, Dharmarajan,Yogeeswari, Perumal
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- Design of novel β-carboline derivatives with pendant 5-bromothienyl and their evaluation as phosphodiesterase-5 inhibitors
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New derivatives with the tetrahydro-β-carboline-imidazolidinedione and tetrahydro-β-carboline-piperazinedione scaffolds and a pendant bromothienyl moiety at C-5/C-6 were synthesized and tested for their ability to inhibit PDE5 in vitro. The following SAR can be concluded: The tetracyclic scaffold is essential for PDE5 inhibition; the ethyl group is the most suitable among the adopted N-substituents on the terminal ring (hydantoin/ piperazinedione); the appropriate stereochemistry of C-5/C-6 derived from the aldehyde rather than C-11a/C-12a derived from tryptophan appears crucial for inhibition of PDE5; surprisingly, derivatives with the hydantoin terminal ring are more active than their analogs with the piperazinedione ring; the selectivity versus PDE5 relative to PDE11 with cGMP as a substrate is mainly a function of the substitution and stereochemistry pattern of the external ring, in other words of the interaction with the H-loop residues of the isozymes. Thirteen derivatives showed PDE5 inhibitory activity with IC50 values in the range of 0.16-5.4 μm. Compound 8 was the most potent PDE5 inhibitor and showed selectivity towards PDE5 versus other PDEs, with a selectivity index of 49 towards PDE5 rather than PDE11 with cGMP as the substrate. New derivatives with the tetrahydro-β-carboline-imidazolidinedione and tetrahydro-β-carboline-piperazinedione scaffolds and a pendant bromothienyl moiety at C-5/C-6 were synthesized and tested for their ability to inhibit PDE5 in vitro. Of these, 13 derivatives showed PDE5 inhibitory activity with IC 50 values in the range of 0.16-5.4 μm and with compound 8 being the most active derivative. The tetracyclic scaffold was shown to be essential for PDE5 inhibition. Copyright
- El-Gamil, Dalia S.,Ahmed, Nermin S.,Gary, Bernard D.,Piazza, Gary A.,Engel, Matthias,Hartmann, Rolf W.,Abadi, Ashraf H.
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- Total synthesis and absolute configuration of nocardioazine B
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The first total synthesis of the indole alkaloid nocardioazine B was accomplished in 10 steps with an overall yield of 11.8%, establishing the absolute stereochemistry of the natural product. The Royal Society of Chemistry 2012.
- Wang, Mingzhong,Feng, Xiangyang,Cai, Liangzhen,Xu, Zhengshuang,Ye, Tao
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- Exploring the PDE5 H-pocket by ensemble docking and structure-based design and synthesis of novel β-carboline derivatives
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By studying the co-crystal information of interactions between PDE5 and its inhibitors, forty new tetrahydro-β-carbolines based-analogues were synthesized, and tested for their PDE5 inhibition. Some compounds were as active as tadalafil in inhibiting PDE5 and of better selectivity profile particularly versus PDE11A, the nature of the terminal ring and its nitrogen substituent are the main determinants of selectivity. Ensemble docking confirmed the role of H-loop closed conformer in activity versus its occluded and open forms. Conformational studies showed the effect of bulkiness of the terminal ring N-alkyl substituent on the formation of stable enzyme ligands conformers. The difference in potencies of hydantoin and piperazinedione analogues, together with the necessity of C-5/C-6 R-absolute configuration has been revealed through molecular docking.
- Ahmed, Nermin S.,Ali, Amal H.,El-Nashar, Shreen M.,Gary, Bernard D.,Fajardo, Alexandra M.,Tinsley, Heather N.,Piazza, Gary A.,Negri, Matthias,Abadi, Ashraf H.
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- Indole Alkaloids from a Soil-Derived Clonostachys rosea
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Clonorosins A ( 1 ) and B ( 2 ), two novel indole alkaloids featuring unprecedented 6/5/6/6/5 and 6/5/5 cores, together with seven known indole-linked 2,5-diketopiperazine alkaloids ( 3 - 9 ), were isolated from the soil-derived fungusClonostachys roseaYRS-06. The new structures were proposed through HR-MS, NMR, and ECD spectroscopic data. They were established by comparing the calculated NMR, ECD, and specific rotation data with the experimental. To assist in determining the absolute configuration of the chiral carbon in the side chain of 2,5-diketopiperazine derivatives, flexible analogues 3i - 3iv were synthesized and analyzed. 1 was active againstFusarium oxysporumwith an MIC value of 50 μg/mL. 7 and 8 showed excellent activity against human HeLa and HepG2 cells with IC50values of 0.12-0.60 μM.
- Fang, Jianguo,Jiang, Chun-Xiao,Miao, Ya-Mei,Ren, Hao,Tian, Li-Li,Wang, Xiaolei,Wu, Quan-Xiang,Xu, Qianhe,Yu, Bo,Yu, Zhen-Qing,Zhang, Jin Z.,Zhang, Jiwen,Zhao, Chun,Zhou, Pan-Pan
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- Total Synthesis of Homo-and Heterodimeric Bispyrrolidinoindoline Dioxopiperazine Natural Products
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Total synthesis and structural confirmation of homo-and heterodimeric bispyrrolidinoindoline dioxopiperazine alkaloids isolated from fungi and bacteria, namely, ditryptoleucine A, ditryptoleucine B (11), the N,N′-bis-demethylated analogue (+)-12, (-)-dibrevianamide F (13), (-)-SF-5280-451 (14), tetratryptomycin A (15), (-)-Tryprophenaline (17), and (-)-SF-5280-415 (18), has been carried out starting from the corresponding bispyrrolidinoindolines derived from tryptophan. Our efforts to synthesize all possible diastereomers of the natural ditryptoleucine isolates uncovered structural factors that determine the rate and efficiency of dioxopiperazine ring formation, leading in some cases to mixtures of diastereomers by concomitant epimerization, to the formation of their putative monomeric dioxopiperazine dipeptide biogenetic precursors, and to the alternative formation of a dimer with a fused 1,3,5-Triazepan-6-one heterocycle.
- álvarez, Rosana,Alvarez, Susana,Areal, Andrea,De Lera, ángel R.,Domínguez, Marta,Vendrig, Pim
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supporting information
p. 1725 - 1737
(2021/06/28)
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- Production process of tadalafil bulk drug
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The invention belongs to the technical field of medicines, and particularly relates to a production process of a tadalafil bulk drug. The production process of the tadalafil bulk drug comprises the following steps: A1, carrying out an esterification reaction on methanol and D-tryptophan to obtain an intermediate I; A2, performing a condensation reaction on the intermediate I and heliotropin to obtain an intermediate II; A3, performing an acylation reaction on the intermediate II and chloroacetyl chloride to obtain an intermediate III; and A4, carrying out a cyclization reaction on the intermediate III and monomethylamine to obtain the tadalafil bulk drug. According to the method, a reaction path is reasonably selected, and meanwhile, the process details of each reaction step are deeply optimized, so high purity and yield of a product of each step of reaction can be obtained, the prepared tadalafil bulk drug is low in cost and good in stability, the economical efficiency of the whole reaction path is improved, and production cost is reduced.
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Paragraph 0014-0015
(2020/07/02)
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- An increase in side-group hydrophobicity largely improves the potency of ritonavir-like inhibitors of CYP3A4
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Identification of structural determinants required for potent inhibition of drug-metabolizing cytochrome P450 3A4 (CYP3A4) could help develop safer drugs and more effective pharmacoenhancers. We utilize a rational inhibitor design to decipher structure-activity relationships in analogues of ritonavir, a highly potent CYP3A4 inhibitor marketed as pharmacoenhancer. Analysis of compounds with the R1 side-group as phenyl or naphthalene and R2 as indole or naphthalene in different stereo configuration showed that (i) analogues with the R2-naphthalene tend to bind tighter and inhibit CYP3A4 more potently than the R2-phenyl/indole containing counterparts; (ii) stereochemistry becomes a more important contributing factor, as the bulky side-groups limit the ability to optimize protein-ligand interactions; (iii) the relationship between the R1/R2 configuration and preferential binding to CYP3A4 is complex and depends on the side-group functionality/interplay and backbone spacing; and (iv) three inhibitors, 5a-b and 7d, were superior to ritonavir (IC50 of 0.055–0.085 μM vs. 0.130 μM, respectively).
- Samuels, Eric R.,Sevrioukova, Irina F.
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- Extending the use of tadalafil scaffold: Development of novel selective phosphodiesterase 5 inhibitors and histone deacetylase inhibitors
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Herein we present the synthesis and characterization of a novel chemical series of tadalafil analogues that display different pharmacological profiles. Compounds that have the 6R, 12aR configuration and terminal carboxylic acid group at the side chain arising from the piperazinedione nitrogen were potent PDE5 inhibitors, with compound 11 having almost equal potency to tadalafil and superior selectivity over PDE11, the most common off–target for tadalafil. Modifying the stereochemistry into 6S, 12aS configuration and adopting the hydroxamic acid moiety as a terminal group gave rise to compounds that only inhibited HDAC. Dual PDE5/HDAC inhibition could be achieved with compounds having 6R, 12aR configuration and hydroxamic acid moiety as a terminal group. The anticancer activity of the synthesized compounds was evaluated against a diverse number of cell lines of different origin. The compounds elicited anticancer activity against cell lines belonging to lymphoproliferative cancer as well as solid tumors. Despite the previous reports suggesting anticancer activity of PDE5 inhibitors, the growth inhibitory activity of the compounds seemed to be solely dependent on HDAC inhibition. Compound 26 (pan HDAC IC50 = 14 nM, PDE5 IC50 = 46 nM) displayed the most potent anticancer activity in the present series and was shown to induce apoptosis in Molt-4 cells. HDAC isoform selectivity testing for compound 26 showed that it is more selective for HDAC6 and 8 over HDAC1 by more than 20-fold.
- Abadi, Ashraf H.,Abdel-Halim, Mohammad,Ahmed, Nermin S.,Chen, Yu-Cheng,ElHady, Ahmed K.,Engel, Matthias,Keeton, Adam B.,Liu, Yi-Chang,Piazza, Gary A.,Shih, Shou-Ping
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- Histidine triad nucleotide-binding proteins HINT1 and HINT2 share similar substrate specificities and little affinity for the signaling dinucleotide Ap4A
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Human histidine triad nucleotide-binding protein 2 (hHINT2) is an important player in human mitochondrial bioenergetics, but little is known about its catalytic capabilities or its nucleotide phosphoramidate prodrug (proTide)-activating activity akin to the cytosolic isozyme hHINT1. Here, a similar substrate specificity profile (kcat/Km) for model phosphoramidate substrates was found for hHINT2 but with higher kcat and Km values when compared with hHINT1. A broader pH range for maximum catalytic activity was determined for hHINT2 (pK1?=?6.76?±?0.16, pK2?=?8.41?±?0.07). In addition, the known hHINT1-microphthalmia-inducing transcription factor-regulating molecule Ap4A was found to have no detectable binding to HINT1 nor HINT2 by isothermal titration calorimetry. These results demonstrate that despite differences in their sequence and localization, HINT1 and HINT2 have similar nucleotide substrate specificities, which should be considered in future proTide design and in studies of their natural function.
- Strom, Alexander,Tong, Cher Ling,Wagner, Carston R.
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p. 1497 - 1505
(2020/02/25)
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- Preparation method of tadalafil and intermediate of tadalafil
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The invention relates to a preparation method of a selective and reversible inhibitor tadalafil of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase 5 (PDE5). The method comprises the following steps: carrying out an esterification reaction on D-tryptophan as an initial raw material and methanol under catalysis of sulfuric acid to generate D-tryptophan methyl ester (an intermediate1); carrying out a Pictet-Spengler (P-S) reaction on the D-tryptophan methyl ester and heliotropin to prepare (1R,3R)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester hydrochloride (an intermediate 2); carrying out an amidation reaction on the (1R,3R)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester hydrochloride and chloroacetyl chloride to prepare (1R,3R)-1-(1,3-benzodioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester (an intermediate 3); andfinally carrying out a cyclization reaction on the (1R,3R)-1-(1,3-benzodioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester and a methylamine alcohol solution to obtain the tadalafil. The method provided by the invention has the advantages of easily available raw materials, simple operation, greenness, environmental protection and low costs, andis suitable for industrial production.
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Paragraph 0026-0034
(2019/11/20)
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- Design, synthesis, and molecular docking studies of N-(9,10-anthraquinone-2-carbonyl)amino acid derivatives as xanthine oxidase inhibitors
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A series of N-(9,10-anthraquinone-2-carbonyl)amino acid derivatives (1a–j) was designed and synthesized as novel xanthine oxidase inhibitors. Among them, the L/D-phenylalanine derivatives (1d and 1i) and the L/D-tryptophan derivatives (1e and 1j) were effective with micromolar level potency. In particular, the L-phenylalanine derivative 1d (IC50?=?3.0?μm) and the D-phenylalanine derivative 1i (IC50?=?2.9?μm) presented the highest potency and were both more potent than the positive control allopurinol (IC50?=?8.1?μm). Preliminary SAR analysis pointed that an aromatic amino acid fragment, for example, phenylalanine or tryptophan, was essential for the inhibition; the D-amino acid derivative presented equal or greater potency compared to its L-enantiomer; and the 9,10-anthraquinone moiety was welcome for the inhibition. Molecular simulations provided rational binding models for compounds 1d and 1i in the xanthine oxidase active pocket. As a result, compounds 1d and 1i could be promising lead compounds for further investigation.
- Zhang, Ting-Jian,Li, Song-Ye,Yuan, Wei-Yan,Zhang, Yi,Meng, Fan-Hao
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p. 893 - 901
(2018/03/21)
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- Asymmetric synthesis of 1-aryl-1H-pyridine[3,4-b]indole-3-carboxylic acid methyl ester derivatives
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The invention discloses an asymmetric synthesis method for synthesizing 1-aryl-1H-pyridine[3,4-4]indole-3-carboxylic acid methyl ester derivatives containing two chiral centers from (R)methyl-2-amino-3-(1H-indol-3-yl)propanoate and aldehyde as main starting materials under catalysis of a catalyst, namely, chiral Lewis acid formed by a chiral tridentate ligand compound L and Ti(O-iPr)4. Compared with the prior art, the method has the advantages that the reaction yield is increased and the reaction non-correspondence selectivity is remarkably improved.
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Paragraph 0020
(2018/04/01)
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- Exciton-Coupled Circular Dichroism Characterization of Monotopically Binding Guests in Host?Guest Complexes with a Bis(zinc porphyrin) Tweezer
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A stiff-stilbene-linked bisporphyrin tweezer with inherent helicity was used for exciton-coupled circular dichroism (ECCD) characterization of a series of monotopically binding amine guest molecules. CD signals were observed for a variety of monoamines at relatively low tweezer/amine (host/guest) ratios between 1 : 10 to 1 : 70. For the amines producing the most intense CD signals, a binding stoichiometry of 1 : 2 was found. A likely explanation is the presence of guest-guest interactions in the complexes. This is supported by the correlation observed between CD signal intensity and magnitude of possible noncovalent binding between the guests, which can be divided into three groups showing no, moderate and strong response, respectively. Further support for this rationalization comes from molecular modelling.
- Olsson, Sandra,Sch?fer, Clara,Blom, Magnus,Gogoll, Adolf
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p. 1169 - 1178
(2019/01/04)
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- Design, synthesis, and evaluation of novel Akt1 inhibitors based on an indole scaffold
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A new series of potential Akt1 inhibitors with indole scaffold were designed and synthesized. The antiproliferative activity against PC-3 cell line and enzyme inhibitory activity against Akt1 were evaluated. Among them, some compounds showed much more potent antiproliferative activity and stronger Akt1 inhibitory activity compared to the positive control of GSK690693. In particular, compound 19b exhibited the most potent inhibitory activity against Akt1 with inhibition rate of 70.3% at a concentration of 10?nm. Furthermore, compound 19b could dose dependently reduce the phosphorylation of the downstream GSK3β protein in the PC-3 cell line and displayed fivefold higher antiproliferative activity against PC-3 cell line with IC50 value of 3.1?±?0.1?μm than positive control (15.5?±?0.4?μm). Herein, compound 19b may serve as a promising lead for further optimization and development of novel Akt1 inhibitors based on an indole scaffold.
- Yang, Dezhi,Tong, Dongdong,Zhang, Qian,Wang, Yongtao,Sun, Jing,Zhang, Fenghe,Zhao, Guisen
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p. 791 - 803
(2017/09/30)
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- Non-correspondence selective synthesis of 1-aryl-1H-pyridine[3,4-b]indole derivative
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The invention discloses an asymmetric synthesis method for synthesizing 1-aryl-1H-pyridine[3,4-b]indole-3-carboxylic acid methyl ester derivatives containing two chiral centers by taking (R)-tryptophan methyl ester and aldehyde as main starting raw materials, taking chiral Lewis acid Salen-Mn as a catalyst and taking (R)-alpha-methyl-4-nitrophenylacetic acid as a chiral additive. Compared with the prior art, the reaction yield is improved and the non-correspondence selectivity of the reaction is remarkably improved.
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Paragraph 0025
(2018/03/28)
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- Synthesis of novel C3-linked β-carboline-pyridine derivatives employing khronke reaction: DNA-binding ability and molecular modeling studies
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A series of novel C3-linked β-carboline pyridine (BCP) derivatives have been synthesized via modified Khronke reaction and studied for their DNA-binding affinities. Among all the derivatives, compound 12f has shown significant enhancement in the DNA-binding affinity (ΔTm:6.3 oC and 6.5 oC at 0 h and 18 h incubation) in comparison to the standard Doxorubicin (ΔTm:2.4 oC and 2.6 oC at 0 h and 18 h incubation). This result suggested a strong intercalation with DNA double helix. Moreover, molecular modeling studies also showed that the planar β-carboline ring establishes π-π interactions with DNA base pairs and these interactions are further extended due to the presence of pyridine ring. The DNA intercalation has also been investigated for these compounds by molecular docking and the results are in agreement with thermal denaturation data.
- Shankaraiah, Nagula,Sharma, Pankaj,Pedapati, Srinivas,Nekkanti, Shalini,Srinivasulu, Vunnam,Kumar, Niggula Praveen,Kamal, Ahmed
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p. 335 - 342
(2016/04/04)
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- Dipeptide analogs for treating conditions associated with amyloid fibril formation
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Dipeptide analogs comprising a tryptophan (Trp) moiety coupled to a beta-sheet breaker moiety derived from alpha-aminoisobutyric acid (Aib) are disclosed. The dipeptide analogs exhibit an improved performance in inhibiting amyloid fibril formation, as compared to previously described dipeptides. Compositions containing the dipeptide analogs and uses thereof in treating amyloid-associated diseases and disorders are also disclosed.
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Page/Page column 21; 22
(2015/09/22)
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- Design, synthesis and evaluation of novel indole derivatives as AKT inhibitors
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Herein, we describe the discovery and synthesis of a new series of 1,2,4,7-tetra-substituted indole derivatives as novel AKT inhibitors by optimization of a weak hit methyl 4-(2-aminoethoxy)-1H-indole-2-carboxylate (1). Both representative compounds 6a and 6o exhibited the most potent inhibitory activities against AKT1, with inhibition rates of 72.5% and 78.6%, respectively, at concentrations of 10 nM. In addition, compounds 6a and 6o also potently inhibited the phosphorylation of the downstream GSK3 protein and displayed slightly better anti-proliferative activities in a prostate cancer cell line.
- Yang, Dezhi,Wang, Peng,Liu, Jianzhen,Xing, Hualu,Liu, Yang,Xie, Wencheng,Zhao, Guisen
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p. 366 - 373
(2014/01/17)
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- Improved synthesis of tadalafil using dimethyl carbonate and ionic liquids
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An improved synthesis of tadalafil, a drug for the treatment of male erectile dysfunction, involves the use of safer solvents and reagents as well as a reduced number of steps.
- Earle, Martyn J.,Noe, Marco,Perosa, Alvise,Seddon, Kenneth R.
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p. 1204 - 1211
(2014/01/06)
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- Design, synthesis and anti-itch activity evaluation of aromatic amino acid derivatives as gastrin-releasing peptide receptor antagonists
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Eight aromatic amino acid derivatives (9a-9h) as gastrin-releasing peptide receptor (GRPR) antagonists were designed and synthesized. For the design, the tertiary structure of GRPR was predicted by blast searching in the premise of 1u19 protein as the template. Eight target compounds were docked into the binding pocket to investigate their possible binding interactions. Their anti-itch activities were tested by intrathecal injection using Kunming mice as experimental animals and chloroquine phosphate as a modeling medium. Compounds 9e and 9f significantly inhibited scratching behaviors. The anti-itch activities of these compounds decreased with the following sequence: 9e > 9f = 9d > 9b > 9g > 9a > 9h > 9c predicted by computer-aided drug design (CADD) and 9e > 9f > 9b > 9h > 9g > 9d > 9a > 9c evaluated by preliminary test. They were broadly in line with activity order pretested by CADD. It showed that the predicted tertiary structure of GRPR could be used for antipruritic drug design.
- Yao, Ri-Sheng,Li, Ting-Ting,Xu, Jun,Jiang, Lai-En,Ruan, Ban-Feng
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p. 865 - 873
(2012/10/29)
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- Chiral indolo[3,2-f][3]benzazecine-type dopamine receptor antagonists: Synthesis and activity of racemic and enantiopure derivatives
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Racemic and enantiopure 8-substituted derivatives of the lead dopamine receptor antagonist LE 300 (1) were prepared, and their affinities for the dopamine receptors (D1-D5) were tested. The separate enantiomers showed significantly different affinities; the (8S)-methyl and (8R)-hyroxymethyl derivatives where the substituents point below the reference plane of the indolo[3,2-f][3]benzazecine scaffold were markedly more active than their enantiomeric counterparts. The racemic 8-carboxy derivative was shown to be selective for the D5-receptor, even against D1.
- Robaa, Dina,Enzensperger, Christoph,Eldin Abulazm, Shams,Hefnawy, Mohamed M.,El-Subbagh, Hussein I.,Wani, Tanveer A.,Lehmann, Jochen
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supporting information; experimental part
p. 7422 - 7426
(2011/12/16)
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- Synthesis and molecular modeling of novel tetrahydro-β-carboline derivatives with phosphodiesterase 5 inhibitory and anticancer properties
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New derivatives based upon the tetrahydro-β-carboline-hydantoin and tetrahydro-β-carboline-piperazinedione scaffolds were synthesized. All compounds were evaluated for their ability to inhibit PDE5 in vitro, and numerous compounds with IC50 values in the low nanomolar range were identified including compounds derived from l-tryptophan. Compounds with high potency versus PDE5 were then evaluated for inhibitory activity against other PDEs to assess isozyme selectivity. Compound 5R,11aS-5-(3,4-dichlorophenyl)-2- ethyl-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b] indole-1,3(2H)dione 14 showed a selectivity index of >200 for cGMP hydrolysis by PDE5 versus PDE11. Meanwhile, 6R,12aR-6-(2,4-dichlorophenyl)-2-ethyl-2,3,6, 7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4dione 45 demonstrated strong potency for inhibition of PDE11 with an IC50 value of 11 nM, representing the most potent PDE11 inhibitor thus far reported. Docking experiments differentiated between active and inactive analogues and revealing the conformational, steric, and lipophilic necessities for potent PDE5 inhibition. Many derivatives, including potent PDE5 inhibitors, were able to inhibit the growth of the MDA-MB-231 breast tumor cell line with low micromolar potency.
- Mohamed, Heba A.,Girgis, Nancy M. R.,Wilcken, Rainer,Bauer, Matthias R.,Tinsley, Heather N.,Gary, Bernard D.,Piazza, Gary A.,Boeckler, Frank M.,Abadi, Ashraf H.
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experimental part
p. 495 - 509
(2011/04/15)
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- Design, synthesis and structure-activity relationship of functionalized tetrahydro-β-carboline derivatives as novel PDE5 inhibitors
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Starting from tadalafil as a template, a series of functionalized tetrahydro-β-carboline derivatives have been prepared and identified as novel potent and selective PDE5 inhibitors. Replacing the 3,4- methylenedioxyphenyl at position 6 of tadalafil, together with elongation of the N2-methyl substituent and manipulation of the stereochemical aspects of the two chiral carbons led to the identification of compound XXI, a highly potent PDE5 inhibitor (IC50 = 3 nM). Compound XXI was also highly selective for PDE5 versus PDE3B, PDE4B, and PDE11A, with a selectivity index of 52 and 235 towards PDE5 rather than PDE11 with both cAMP and cGMP as substrate, respectively.
- Ahmed, Nermin S.,Gary, Bernard D.,Tinsley, Hethar N.,Piazza, Gary A.,Laufer, Stefan,Abadi, Ashraf H.
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scheme or table
p. 149 - 157
(2011/10/05)
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- TETRAHYDRO-β-CARBOLINE DERIVATIVES, SYNTHESIS AND USE THEREOF
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Certain 2-halophenyl, 2,4-dihalophenyl (e.g. 2,4-dichlorophenyl), 3,4- dichlorophenyl (e.g.3,4-dichlorophenyl), 2,6-dichlorophenyl (2,6-dichlorophenyl) and 2,5-diakoxyphenyl (e.g. 2,5-dimethoxyphenyl) derivatives of tetrahydro-β-carbolines are provided, along with their pharmaceutically acceptable salts; prodrugs and solvates, and compositions containing the compounds. The compounds are useful for the prevention and treatment of cancer, and other indications where PDE5 inhibitors have shown benefits including erectile dysfunction, pulmonary hypertension, enhancing cognitive function, cystic fibrosis, or enhancing the activity of conventional chemotherapeutic drugs. Methods for fabricating the compounds are also provided.
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- Synthesis, molecular modeling and biological evaluation of novel tadalafil analogues as phosphodiesterase 5 and colon tumor cell growth inhibitors, new stereochemical perspective
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The synthesis of novel tadalafil analogues in which the benzodioxole moiety is replaced by 2-bromophenyl; the chiral carbons swing from R,R to R,S, S,R and S,S; the piperazinedione ring is maintained or reduced to the 5-membered imidazolidinedione or thioxoimidazolinone is described. The prepared analogues were evaluated for their capacity to inhibit the cyclic guanosine monophosphate (cGMP) selective phosphodiesterase 5 (PDE5) isozyme and the growth of human HT-29 colon adenocarcinoma cells. The R absolute configuration of C-5 in the β-carboline-hydantoin and C-6 in the β-carboline-piperazinedione derivatives was found to be essential for the PDE5 inhibition. In addition, tadalafil analogues that were synthesized from l-tryptophan were more active than those derived from d-tryptophan, which is of economic value and expands the horizon for the discovery of new carbolines as PDE5 inhibitors. While some analogues displayed potent tumor cell growth inhibitory activity, there was no apparent correlation with their PDE5 inhibitory activity, which leads us to conclude that other PDE isozymes or PDE5 splice variants may be involved.
- Abadi, Ashraf H.,Gary, Bernard D.,Tinsley, Heather N.,Piazza, Gary A.,Abdel-Halim, Mohammad
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scheme or table
p. 1278 - 1286
(2010/06/14)
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- Synthesis and cytotoxicity evaluation of (tetrahydro-β-carboline)-1,3,5-triazine hybrids as anticancer agents
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A series of tetrahydro-β-carbolines and 1,3,5-triazine hybrids have been synthesized and evaluated for their cytotoxicity against a panel of eight human cancer cell lines and normal human fibroblasts (NIH3T3). It led us to discovery of racemic compounds 69, 71 and 75, which are selectively cytotoxic towards KB (oral cancer) cell line with IC50 values of 105.8, 664.7 and 122.2?nM, respectively; while their enantiopure forms are less active and not selective. Enantiopure compound 42 showed 2.5 times more selectivity towards MCF7 cells over normal fibroblast NIH3T3 cells with an IC50 value of 740?nM, also arrests cell cycle in G1 phase and induces apoptosis in MCF7 and MDA MB231cell lines.
- Kumar, Ravi,Gupta, Leena,Pal, Pooja,Khan, Shahnawaz,Singh, Neetu,Katiyar, Sanjay Babu,Meena, Sanjeev,Sarkar, Jayanta,Sinha, Sudhir,Kanaujiya, Jitendra Kumar,Lochab, Savita,Trivedi, Arun Kumar,Chauhan, Prem M.S.
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experimental part
p. 2265 - 2276
(2010/06/17)
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- Synthesis and biological evaluation of indolyl glyoxylamides as a new class of antileishmanial agents
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A series of indolylglyoxylamide derivatives have been synthesized and evaluated in vitro against amastigote form of Leishmania donovani. Compound 8c has been identified as the most active analog of the series with IC50 value of 5.17 μM and SI value of 31.48, and is several folds more potent than the standard drugs sodium stilbogluconate and pentamidine.
- Chauhan, Shikha S.,Gupta, Leena,Mittal, Monika,Vishwakarma, Preeti,Gupta, Suman,Chauhan, Prem M.S.
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scheme or table
p. 6191 - 6194
(2010/12/18)
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- A novel access to arylated and heteroarylated beta-carboline based PDE5 inhibitors
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Starting from a previously reported lead compound GR30040X (a hydantoin tetrahydro-β-carboline derivative with a 4- pyridinyl ring at C- 5), a series of structurally related tetrahydro-β-carboline derivatives were prepared. The tetrahydro- β-carboline skeleton was fused either to a hydantoin or to a piperazindione ring, the pendant aryl group attached to C-5 or C-6 was changed to a 3, 4-dimethoxyphenyl or a 3-pyridinyl ring; different N-substituents on the terminal ring were introduced, a straight chain ethyl group, a branched tert. butyl and P-chlorophenyl group rather than n-butyl group of the lead compound. All four possible diastereomers of target tetrahydro-β-carboline derivatives were prepared, separated by column chromatography and the significance of these stereochemical manipulations was studied. Synthesized compounds were evaluated for their inhibitory effect versus PDE5. Seven hits were obtained with appreciable inhibitory activity versus PDE5 with IC50s 0.14 - 4.99 μM.
- Ahmed, Nermin S.,Gary, Bernard D.,Piazza, Gary A.,Tinsley, Heather N.,Laufer, Stefan,Abadi, Ashraf H.
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scheme or table
p. 374 - 387
(2012/04/05)
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- Novel HDAC6 isoform selective chiral small molecule histone deacetylase inhibitors
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In an effort to identify HDAC isoform selective inhibitors, we designed and synthesized novel, chiral 3,4-dihydroquinoxalin-2(1H)-one and piperazine-2,5-dione aryl hydroxamates showing selectivity (up to 40-fold) for human HDAC6 over other class I/IIa HDACs. The observed selectivity and potency (IC50 values 10-200 nM against HDAC6) is markedly dependent on the absolute configuration of the chiral moiety, and suggests new possibilities for use of chiral compounds in selective HDAC isoform inhibition.
- Smil, David V.,Manku, Sukhdev,Chantigny, Yves A.,Leit, Silvana,Wahhab, Amal,Yan, Theresa P.,Fournel, Marielle,Maroun, Christiane,Li, Zuomei,Lemieux, Anne-Marie,Nicolescu, Alina,Rahil, Jubrail,Lefebvre, Sylvain,Panetta, Anthony,Besterman, Jeffrey M.,Déziel, Robert
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scheme or table
p. 688 - 692
(2009/08/15)
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- New chiral building blocks of β-peptoid analogs
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The synthesis of chiral functionalized β-amino esters via the hydride reductive amination of chiral allenes was explored. These compounds can be regarded as β-peptoids building blocks bearing a chiral side chain at the nitrogen and at the same time retaining the β-amino acid side chain. β-Enamino esters were obtained from the nucleophilic addition of α-amino esters (l-Ala, d-Ala, l-Phe, l-Leu, l-Trp and d-Trp methyl esters) to 2,3-allenoates bearing a chiral auxiliary, which determines the stereochemistry outcome of the subsequent reduction reaction. It was also demonstrated that in the reduction of β-enamino esters derived from l-Pro and d-Pro methyl esters the chirality of the new chiral center is controlled by the α-amino ester moiety.
- Cardoso, Ana Lúcia,Lopes, Susana M.M.,Matos Beja, Ana,Ramos Silva, Manuela,de los Santos, Jesús M.,Pinho e Melo, Teresa M.V.D.,Palacios, Francisco
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body text
p. 9116 - 9124
(2010/01/16)
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- Synthesis of diketopiperazine-based carboline homodimers and in vitro growth inhibition of human carcinomas
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Starting from d- or l-tryptophan, we have synthesized and characterized six compounds 2.29-2.31a and b that belong to a class of nitrogen heterocycles: the carboline-based homodimers. Each individual homodimer features a 1,3-trans relationship on each side of the central diketopiperazine core, but differs in absolute stereochemistry and also in substitution on the 4′ and 4″ oxygens (-Bn, -CH3, or -H). The in vitro cytotoxicity of the six compounds was evaluated by measuring the growth inhibition in NCI-H520 and PC-3 human carcinoma cells. Phenol 2.30a inhibited cancer cell growth approximately three times better than its enantiomer 2.30b and possessed a GI50 comparable to the clinically used agent etoposide in both cell lines. We have concluded that both the stereochemistry imparted by l-tryptophan and the presence of hydroxy substituents at the 4′ and 4″ positions are necessary to generate cytotoxic properties in the homodimer class. We are now employing 2.30a as a new lead compound in our efforts to discover improved indole-based cancer chemotherapeutics.
- Deveau, Amy M.,Costa, Nancy E.,Joshi, Elizabeth M.,Macdonald, Timothy L.
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supporting information; experimental part
p. 3522 - 3525
(2009/04/06)
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- ONCOGENIC-RAS-SIGNAL DEPENDENT LETHAL COMPOUNDS
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Compounds with cancer cell specific lethality are provided. In particular, RAS-selective lethal compounds and compositions are provided. Also provided are methods of screening for such compounds and methods of treating a condition in a mammal, by administering to the mammal a therapeutically effective amount of such compounds or compositions.
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Page/Page column 107
(2008/12/08)
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- Synthesis of 2-[3-(7-Chloro-quinolin-4-ylamino)-alkyl]-1-(substituted phenyl)-2,3,4,9-tetrahydro-1H-β-carbolines as a new class of antimalarial agents
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A series of hybrid molecules 2-[3-(7-Chloro-quinolin-4-ylamino)-alkyl]-1-(substituted phenyl)-2,3,4,9-tetrahydro-1H-β-carbolines have been synthesized and screened for their in vitro antimalarial activity against chloroquine-sensitive strains of Plasmodium falciparum. Compounds 26, 32, and 34 have shown MIC in the range of 0.05-0.11 μM and are in vitro several folds more active than chloroquine.
- Gupta, Leena,Srivastava, Kumkum,Singh, Shubhra,Puri,Chauhan, Prem M.S.
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scheme or table
p. 3306 - 3309
(2009/04/11)
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- BENZODIAZEPINE AND BENZOPIPERAZINE ANALOG INHIBITORS OF HISTONE DEACETYLASE
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This invention relates to compounds for the inhibition of histone deacetylase More particularly, the invention provides for compounds of formula (I): wherein A, B, D, E, X1, X2, X3, X4 and n are as defined in the specification A method of inhibiting histone deacetylase in a cell, the method comprising contacting the cell with a compound of formula (I), in an amount sufficient to inhibit histone deacetylase, is also disclosed.
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Page/Page column 109
(2010/11/26)
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- Synthesis of chiral 3-substituted hexahydropyrroloindoline via intermolecular cyclopropanation
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(Chemical Equation Presented) A new and efficient synthetic route to chiral 3-substituted hexahydropyrroloindoline 18 possessing absolute configurations in accordance with indole alkaloids has been developed from readily available L-tryptophan. The key step relies on the one-pot cascade reaction of oxazolidinone 17 with diazoester, which proceeds through intermolecular cyclopropanation, ring opening, and cyclization.
- Song, Hao,Yang, Jun,Chen, Wei,Qin, Yong
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p. 6011 - 6014
(2007/10/03)
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- NOVEL INDOLOPYRIDINES , BENZOFURANOPYRIDINES AND BENZOTHIENOPYRIDINES
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Compounds of a certain formula (I), in which R1, R2, R3, R4, R5, R6 and X have the meanings indicated in the description, are novel effective compounds with anti-proliferative and/or apoptosis inducing activity.
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Page/Page column 34
(2008/06/13)
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- Utilizing the intramolecular Fukuyama-Mitsunobu reaction for a flexible synthesis of novel heterocyclic scaffolds for peptidomimetic drug design
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We report the synthesis of the novel scaffolds pyrazino[1,2-b]isoquinoline and pyrrolo[1,2-a]pyrazine displaying the somatostatin pharmacophores. Both classes of compounds contain a pyrazine heterocycle, which can be prepared in a straightforward manner utilizing an intramolecular Fukuyama-Mitsunobu reaction. As both the families derive from amino acids, they can be accessed in high optical purity.
- Zapf, Christoph W.,Del Valle, Juan R.,Goodman, Murray
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p. 4033 - 4036
(2007/10/03)
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- Glutaryl Acylases: One-Reaction Enzymes or Versatile Enantioselective Biocatalysts?
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A significant broad substrate specificity, that crosses over the usual β-lactam derivatives, has been observed with an industrial glutaryl-7-aminocephalosporanic acid acylase (GA). This enzyme possesses significant enantioselective amidase and even esterase activity, with a stereopreference for the S-enantiomer. The easy separation of products from unreacted reagents, possessing different physical-chemical properties, is achieved by solvent extraction, avoiding chromatography or distillation during reaction work-up.
- Raimondi, Stefano,Monti, Daniela,Pagnoni, Ugo Maria,Riva, Sergio
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p. 783 - 789
(2007/10/03)
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- Chemical compounds
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Compounds of the general structural formula (I), and use of the compounds and salts and solvates thereof, as therapeutic agents.
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- Treatment of insulin resistance with growth hormone secretagogues
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This invention is directed to methods of treating insulin resistance in a mammal which comprise administering an effective amount of a compound of formula I, where the variables are defined in the specification, or the stereoisomeric mixtures, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers, or the pharmaceutically acceptable salts and prodrugs thereof to said mammal. The compounds of formula I are growth hormone secretagogues and as such are useful for increasing the level of endogenous growth hormone. In another aspect this invention provides certain intermediates which are useful in the synthesis of the foregoing compounds and certain processes useful for the synthesis of said intermediates and the compounds of formula I. This invention is further directed to methods comprising administering to a human or other animal a combination of a functional somatostatin antagonist such as an alpha-2 adrenergic agonist and a compound of formula I.
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- Heterocyclic compounds
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This invention is directed to compounds of the formula and the pharmaceutically-acceptable salts thereof, where the substituents are as defined in the Specification, which are growth hormone secretogogues and which increase the level of endogenous growth hormone. The compounds of this invention are useful for the treatment and prevention of osteoporosis, congestive heart failure, frailty associated with aging, obesity; accelerating bone fracture repair, attenuating protein catabolic response after a major operation, reducing cachexia and protein loss due to chronic illness, accelerating wound healing, or accelerating the recovery of burn patients or patients having undergone major surgery; improving muscle strength, mobility, maintanence of skin thickness, metabolic homeostasis or renal homeostasis. The compounds of the present invention are also useful in treating osteoporosis when used in combination with: a bisphosphonate compound such as alendronate; estrogen, premarin, and optionally progesterone; an estrogen agonist or antagonist; or calcitonin, and pharmaceutical compositions useful therefor. Further, the present invention is directed to pharmaceutical compositions useful for increasing the endogenous production or release of growth hormone in a human or other animal which comprises an effective amount of a compound of the present invention and a growth hormone secretagogue selected from GHRP-6, Hexarelin, GHRP-1, growth hormone releasing factor (GRF), IGF-1, IGF-2 or B-HT920. The invention is also directed to intermediates useful in the preparation of compounds of formula I.
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- Dipeptides which promote release of growth hormone
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Compounds of formula (I) are growth hormone releasing peptide mimetics which are useful for the treatment and prevention of osteoporosis. STR1
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- The Pent-4-enoyl Group: A Novel Amine-Protecting Group That Is Readily Cleaved under Mild Conditions
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Primary and secondary amines are readily protected as N-pent-4-enoyl derivatives, the resulting N-pent-4-enamides being usually highly crystalline.Deprotection is rapidly and efficiently effected under mild conditions by treatment with 3 equiv of iodine in aqueous THF solution.Although an oxidizing medium, these deprotection conditions do not affect oxidizable functionalities including p-methoxybenzyl ethers and alkyl sulfides.
- Madsen, Robert,Roberts, Carmichael,Fraser-Reid, Bert
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p. 7920 - 7926
(2007/10/03)
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- Asymmetric Syntheses via Heterocyclic Intermediates, XXIV. - Enantioselective Synthesis of (R)-α-Methyltryptophane Methyl Ester and D-Tryptophane Methyl Ester by the Bislactim Ether Route
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Die Titelverbindungen wurden durch asymmetrische Synthese nach der Bislactimether-Methode hergestellt (e.e. ueber 95percent bzw. etwa 90percent).
- Schoellkopf, Ulrich,Lonsky, Ralph,Lehr, Philipp
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p. 413 - 417
(2007/10/02)
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- Syntheses of Substituted L- and D-Tryptophans
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Several 5-substituted nb-methoxycarbonyl-L- and -D-tryptophan derivatives were synthesized from proline by a new route involving electrochemical oxidation, as well as by the known procedures.Removal of the Nb-methoxycarbonyl group was accomplished by treatment with Me3SiI in refluxing chloroform, then alkaline hydrolysis of the methyl esters afforded 5-substituted L- and D-tryptophans with high optical purities.Keywords - L-tryptophan 5-substituted; D-tryptophan 5-substituted; anodic oxidation; N-methoxycarbonyl group deprotection; Fischer indole synthesis; iodotrimethylsilane
- Irie, Kunihiko,Ishida, Akihiko,Nakamura, Tohru,Oh-ishi, Tokuro
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p. 2126 - 2139
(2007/10/02)
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