- First total synthesis of aerucyclamide B
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The first total synthesis of the antimalarial aerucyclamide B has been achieved in 9% overall yield. Two thiazoles and a dipeptide were used to prepare two open precursors of cyclo-Gly-l-allo-Thr-l-Ile-Thz-d-allo-Ile-Thz. Cyclodehydration with Deoxo-Fluor of the β-hydroxyamide present in the macrocycle, rendered aerucyclamide B (67%) and an unexpected fluorous derivative (28%).
- Pe?a, Stella,Scarone, Laura,Manta, Eduardo,Serra, Gloria
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Read Online
- Synthesis of a Common Main Skeleton of Thiostrepton Peptide Antibiotics, A10255G and J
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The synthesis of a common main skeleton of thiostrepton peptides, A10255G and J, containing a few kinds of unusual amino acids is described.
- Shin, Chung-gi,Okumura, Kazuo,Ito, Akio,Nakamura, Yutaka
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Read Online
- Synthesis of cyclohexapeptides as antimalarial and anti-trypanosomal agents
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Cyclohexapeptide analogs of natural products were obtained in very good yields by a combination of solid-phase peptide synthesis, for the linear peptide, and solution cyclization. The activities against Plasmodium falciparum K1, Trypanosoma brucei brucei and murine macrophages (cell line J774) of these novel compounds and azolic macrocycles, previously reported by us, were evaluated. Seven macrocycles showed submicromolar activities against Plasmodium falciparum K1 and a high selectivity (SI > 125) for the parasite. In addition, two compounds displayed one digit micromolar EC50 against T. brucei brucei and satisfactory selectivity (SI 82 and 95). Preliminary structure-activity relationships are presented.
- Pe?a,Fagundez,Medeiros,Comini,Scarone,Sellanes,Manta,Tulla-Puche,Albericio,Stewart,Yardley,Serra
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Read Online
- Synthesis of a Microcystis aeruginosa predicted metabolite with antimalarial activity
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The synthesis of a Microcystis aeruginosa predicted metabolite analog of aerucyclamide B was performed. This hexacyclopeptide was obtained from three heterocyclic building blocks by a convergent macrocycle-assembly methodology. The compound exhibited good in vitro antiplasmodial activity (IC50: 0.18 μM, K1, cholorquine resistant strain).
- Pena, Stella,Scarone, Laura,Manta, Eduardo,Stewart, Lindsay,Yardley, Vanessa,Croft, Simon,Serra, Gloria
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Read Online
- Synthesis and Antiproliferative Activity of Nitric Oxide-Donor Largazole Prodrugs
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The marine natural product Largazole is the most potent Class I HDAC inhibitor identified to date. Since its discovery, many research groups have been attracted by the structural complexity and the peculiar anticancer activity, due to its capability to di
- Borgini, Matteo,Botta, Maurizio,Fabio, Romano Di,Ferrante, Luca,Poggialini, Federica,Summa, Vincenzo,Zamperini, Claudio
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supporting information
p. 846 - 851
(2020/07/14)
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- Total Synthesis of the Post-translationally Modified Polyazole Peptide Antibiotic Goadsporin
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The structurally unique polyazole antibiotic goadsporin contains six heteroaromatic oxazole and thiazole rings integrated into a linear array of amino acids that also contains two dehydroalanine residues. An efficient total synthesis of goadsporin is repo
- Dexter, Hannah L.,Williams, Huw E. L.,Lewis, William,Moody, Christopher J.
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supporting information
p. 3069 - 3073
(2017/03/13)
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- A [...] analogs, its preparation process and its application
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The invention discloses a largazole analogue which contains alkyl disulfide side chains and is represented by formula I, and a preparation method and applications thereof. The largazole analogue possesses relatively high antineoplastic activity and selectivity, can be used for development of antitumor drugs. Raw materials of the largazole analogue are cheap and easily available; and the preparation method is simple, and is a method suitable for industrialization. R in formula represents an alkyl group containing 1 to 8 carbon atoms.
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Paragraph 0128-0130
(2016/10/08)
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- Discovery of Novel Class i Histone Deacetylase Inhibitors with Promising in Vitro and in Vivo Antitumor Activities
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A successful structure-based design of novel cyclic depsipeptides that selectively target class I HDAC isoforms is described. Compound 11 has an IC50 of 2.78 nM for binding to the HDAC1 protein, and the prodrugs 12 and 13 also exhibit promising antiproliferative activities in the nanomolar range against various cancer cell lines. Compounds 12 and 13 show more than 20-fold selectivity toward human cancer cells over human normal cells in comparison with romidepsin (FK228), demonstrating low probability of toxic side effects. In addition, compound 13 exhibits excellent in vivo anticancer activities in a human prostate carcinoma (Du145) xenograft model with no observed toxicity. Thus, prodrug 13 has therapeutic potential as a new class of anticancer agent for further clinical translation.
- Yao, Yiwu,Tu, Zhengchao,Liao, Chenzhong,Wang, Zhen,Li, Shang,Yao, Hequan,Li, Zheng,Jiang, Sheng
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supporting information
p. 7672 - 7680
(2015/10/20)
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- Biological evaluation of new largazole analogues: Alteration of macrocyclic scaffold with click chemistry
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We report the design, synthesis, and biological evaluation of a new series of largazole analogues in which a 4-methylthiazoline moiety was replaced with a triazole and tetrazole ring, respectively. Compound 7 bearing a tetrazole ring was identified to show much better selectivity for HDAC1 over HDAC9 than largazole (10-fold). This work could serve as a foundation for further exploration of selective HDAC inhibitors using a largazole molecular scaffold.
- Li, Xianlin,Tu, Zhenchao,Li, Hua,Liu, Chunping,Li, Zheng,Sun, Qiao,Yao, Yiwu,Liu, Jinsong,Jiang, Sheng
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p. 132 - 136
(2013/03/13)
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- Total synthesis of Microcin B17 via a fragment condensation approach
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The total synthesis of the 43 amino acid antibacterial peptide Microcin B17 (MccB17) is described. The natural product was synthesized via a convergent approach from a heterocycle-derived peptide and peptide thioester fragments prepared via Fmoc-strategy solid phase peptide synthesis (SPPS). Final assembly was achieved in an efficient manner using two Ag(I)-assisted peptide ligation reactions to afford MccB17 in excellent overall yield.
- Thompson, Robert E.,Jolliffe, Katrina A.,Payne, Richard J.
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supporting information; experimental part
p. 680 - 683
(2011/05/03)
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- Largazole and analogues with modified metal-binding motifs targeting histone deacetylases: Synthesis and biological evaluation
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The histone deacetylase inhibitor largazole 1 was synthesized by a convergent approach that involved several efficient and high yielding single pot multistep protocols. Initial attempts using tert-butyl as thiol protecting group proved problematic, and synthesis was accomplished by switching to the trityl protecting group. This synthetic protocol provides a convenient approach to many new largazole analogues. Three side chain analogues with multiple heteroatoms for chelation with Zn2+ were synthesized, and their biological activities were evaluated. They were less potent than largazole 1 in growth inhibition of HCT116 colon carcinoma cell line and in inducing increases in global H3 acetylation. Largazole 1 and the three side chain analogues had no effect on HDAC6, as indicated by the lack of increased acetylation of α-tubulin.
- Bhansali, Pravin,Hanigan, Christin L.,Casero, Robert A.,Tillekeratne, L. M. Viranga
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experimental part
p. 7453 - 7463
(2012/01/03)
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- Total synthesis of largazole and analogues: HDAC inhibition, antiproliferative activity and metabolic stability
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The total synthesis of largazole and four analogues is reported. All analogues were nanomolar HDAC inhibitors. The antiproliferative activity is driven by lipophilicity and cell permeability. In murine liver homogenates, largazole is rapidly metabolized (half-life ≤5 min) to the thiol which has a half-life of 51 min.
- Benelkebir, Hanae,Marie, Sabrina,Hayden, Annette L.,Lyle, Jason,Loadman, Paul M.,Crabb, Simon J.,Packham, Graham,Ganesan
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supporting information; experimental part
p. 3650 - 3658
(2011/08/03)
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- Synthesis and biological characterization of the histone deacetylase inhibitor largazole and C7- modified analogues
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Largazole 4a and analogues with modifications at the C7 position, as well as 2,4′-bithiazole 5a, have been synthesized using an acyclic cross-metathesis of the corresponding depsipeptide structures assembled by N-C6(O) or C15(O)-N lactam formation. Similar to the parent system 4a, the series of largazole depsipeptides 4b-d, but not 2,4′-bithiazole 5a, showed a marked inhibition of recombinant HDAC1 and selectivity over HDAC4, as well as strong pro-apoptotic effects on the NB4 leukemia cell line, but they failed to induce differentiation to mature granulocytes. Functional assays of the analogues correlated with the in vitro activities, as shown by increased H3 and α-tubulin acetylation levels and p21WAF1/CIP1 up-regulation in NB4 cells. The activity of the natural product HDACi largazole 4a is not significantly altered by the presence of groups of different size (H, Et, Ph) at C7 on the dihydrothiazole ring.
- Souto, José A.,Vaz, Esther,Lepore, Ilaria,P?ppler, Ann-Christin,Franci, Gianluigi,álvarez, Rosana,Altucci, Lucia,De Lera, ángel R.
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experimental part
p. 4654 - 4667
(2010/10/02)
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- Oxazole and thiazole combinatorial libraries
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This invention provides a novel method for synthesizing an ensemble of peptides that allows for the generation of an unlimited number of antibiotic compounds. More specifically, the method comprises utilizes synthetic heterocyclic amino acids containing thaizole and/or oxazole as building blocks in a solid phase combinatorial synthesis to yield natural and unnatural antibiotic compounds.
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Page/Page column 9; Sheet 1
(2008/06/13)
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- Efficacious and orally bioavailable thrombin inhibitors based on a 2,5-thienylamidine at the P1 position: Discovery of N-carboxymethyl-D-diphenylalanyl-L-prolyl[(5-amidino-2- thienyl)methyllamide
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Thrombin, a crucial enzyme in the blood coagulation, has been a target for antithrombotic therapy. Orally active thrombin inhibitors would provide effective and safe prophylaxis for venous and arterial thrombosis. We conducted optimization of a highly efficacious benzamidine-based thrombin inhibitor LB30812 (3, Ki = 3 pM) to improve oral bioavailability. Of a variety of arylamidines investigated at the P1 position, 2,5-thienylamidine effectively replaced the benzamidine without compromising the thrombin inhibitory potency and oral absorption. The sulfamide and sulfonamide derivatization at the N-terminal position in general afforded highly potent thrombin inhibitors but with moderate oral absorption, while the well-absorbable N-carbamate derivatives exhibited limited metabolic stability in S9 fractions. The present work culminated in the discovery of the N-carboxymethyl- and 2,5-thienylamidine-containing compound 22 that exhibits the most favorable profiles of anticoagulant and antithrombotic activities as well as oral bioavilability (Ki = 15 pM; F = 43%, 42%, and 15% in rats, dogs, and monkeys, respectively). This compound on a gravimetric basis was shown to be more effective than a low molecular weight heparin, enoxaparin, in the venous thrombosis models of rat and rabbit. Compound 22 (LB30870) was therefore selected for further preclinical and clinical development.
- Lee, Koo,Park, Cheol Won,Jung, Won-Hyuk,Park, Hee Dong,Lee, Sun Hwa,Chung, Kyung Ha,Park, Su Kyung,Kwon, O. Hwan,Kang, Myunggyun,Park, Doo-Hee,Lee, Sang Koo,Kim, Eunice E.,Yoon, Suk Kyoon,Kim, Aeri
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p. 3612 - 3622
(2007/10/03)
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- Thiazole derivatives
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Compounds of the formula: as well as pharmaceutically usable salts and esters thereof, wherein R1, R2and R3have the significance ascribed herein, inhibit binding of adhesive proteins to the surface of different types of cell and accordingly influence cell-cell and cell-matrix interactions. These compounds can be used in the form of pharmaceutical preparations for the control or prevention of neoplasms, tumor metastasing, tumor growth, osteoporosis, Paget's disease, diabetic retinopathy, macular degeneration, restenosis following vascular intervention, psoriasis, arthritis, fibrosis, kidney failure, as well as infection caused by viruses, bacteria or fungi.
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Page column 54
(2010/11/29)
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- Synthesis and structural properties of patellamide A derivatives and their copper(II) compounds.
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The synthesis, characterization and copper(II) coordination chemistry of three new cyclic peptide ligands, PatJ(1) (cyclo-(Ile-Thr-(Gly)Thz-Ile-Thr-(Gly)Thz)), PatJ(2) (cyclo-(Ile-Thr-(Gly)Thz-(D)-Ile-Thr-(Gly)Thz)), and PatL (cyclo-(Ile-Ser-(Gly)Thz-Ile-Ser-(Gly)Thz)) are reported. All of these cyclic peptides and PatN (cyclo-(Ile-Ser-(Gly)Thz-Ile-Thr-(Gly)Thz)) are derivatives of patellamide A and have a [24]azacrown-8 macrocyclic structure. All four synthetic cyclic peptides have two thiazole rings but, in contrast to patellamide A, no oxazoline rings. The molecular structure of PatJ(1), determined by X-ray crystallography, has a saddle conformation with two close-to-coparallel thiazole rings, very similar to the geometry of patellamide D. The two coordination sites of PatJ(1) with thiazole-N and amide-N donors are each well preorganized for transition metal ion binding. The coordination of copper(II) was monitored by UV/Vis spectroscopy, and this reveals various (meta)stable mono- and dinuclear copper(II) complexes whose stoichiometry was confirmed by mass spectra. Two types of dinuclear copper(II) complexes, [Cu(2)(H(4)L)(OH(2))(n)](2+) (n=6, 8) and [Cu(2)(H(2)L)(OH(2))(n)] (n=4, 6; L=PatN, PatL, PatJ(1), PatJ(2)) have been identified and analyzed structurally by EPR spectroscopy and a combination of spectra simulations and molecular mechanics calculations (MM-EPR). The four structures are similar to each other and have a saddle conformation, that is, derived from the crystal structure of PatJ(1) by a twist of the two thiozole rings. The small but significant structural differences are characterized by the EPR simulations.
- Bernhardt, Paul V,Comba, Peter,Fairlie, David P,Gahan, Lawrence R,Hanson, Graeme R,Loetzbeyer, Lutz
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p. 1527 - 1536
(2007/10/03)
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- CARBAPENEM DERIVATIVES
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Novel carbapenem derivatives, represented by the following formula (I), having a substituted or unsubstituted imidazo[5,1-b]thiazolium-6-ylmethyl group at the 2-position are disclosed. The compounds represented by the formula (I) have potent antibacterial activity against a wide spectrum of bacteria from Gram-positive bacteria to Gram-negative bacteria including Pseudomonas aeruginosa and, in addition, have potent antibacterial activity against various beta-lactamase-producing bacteria and MRSA and are very stable against DHP-1.
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- Total synthesis of (+)-nostocyclamide
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The synthesis of (+)-nostocyclamide from the oxazole 1 and thiazoles 2 and 3 is described. The oxazole amino ester 1b was prepared from N-protected alaninamide using a rhodium(II) catalysed N-H insertion reaction as a key step, and the thiazoles 2 and 3 w
- Moody, Christopher J.,Bagley, Mark C.
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p. 601 - 607
(2007/10/03)
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- Dehydrooligopeptides. XIV. Syntheses of 2-[(Z)-1-amino-1-alken-1-yl]oxazole-4-carboxylic acid and the main common skeleton of thiostrepton peptide antibiotics, A10255G and J
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The practical synthesis of a unique dehydropentapeptide (2), the common main skeleton of thiostrepton macrocyclic peptide antibiotics, A10255G and J, is described. Peptide 2 is constructed from a novel 2-[(Z)-1-amino-1-propen-1-yl]oxazole-4-carboxylic aci
- Okumura,Ito,Saito,Nakamura,Shin
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p. 2309 - 2316
(2007/10/03)
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- Synthese natuerlich vorkommender, konformativ eingeschraenkter Oxazol- und Thiazol-haltiger Di- und Tripeptidmimetika
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Keywords: Aminosaeuren; Heterocyclen; Oxidationen; Peptidmimetica; Synthesemethoden
- Videnov, Georgi,Kaiser, Dietmar,Kempter, Christoph,Jung, Guenther
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p. 1604 - 1607
(2007/10/03)
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- DEPSIPEPTIDE ANALOGS OF THE ANTITUMOR DROG DISTAMYCIN CONTAINING THIAZOLE AMINO ACIDS RESIDUES
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Three compounds structurally related to the natural antiviral antitumor drugs netropsin and distamycin have been synthetized.They have been designed starting from 2-(aminomethyl)-thiazole-4 carboxylic acid, gly (Thz), a key element in the structure of hig
- Bailly, Christian,Houssin, Raymond,Bernier, Jean-Luc,Henichart, Jean-Pierre
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p. 5833 - 5844
(2007/10/02)
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- Synthesis of the cyclo- Isomers of Dolastatin 3
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An all-L configuration reverse order of peptide bonding possibility for the cell growth inhibitory (PS system) cyclic peptide dolastatin 3 was eliminated by synthesis of thiazole amino acid containing peptide 2.By employing a series (Schema I) of mixed ca
- Pettit, George R.,Nelson, Paul S.,Holzapfel, Cedric W.
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p. 2654 - 2659
(2007/10/02)
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