- Palladium (II)-catalysed intramolecular C–H functionalizations: Efficient synthesis of kealiinine C and analogues
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An efficient palladium-catalysed C–H functionalization sequence has been developed for the synthesis of 2-aminoimidazole alkaloids (Kealiinine C) and its analogues. This protocol proceeds via iodocyclisation of propargylguanidines followed by intramolecul
- Saha, Debasmita,Stolarzewicz, Izabela,Bahadur, Vijay,Sharma, Upendra K.,Voskressensky, Leonid G.,Sharma, Anuj,Singh, Brajendra K.,Van der Eycken, Erik V.
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p. 233 - 238
(2018/07/03)
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- Hypervalent Iodine(III)-Mediated Cascade Cyclization of Propargylguanidines and Total Syntheses of Kealiinine B and C
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An oxidative cascade cyclization of propargylguanidines promoted by phenyliodonium diacetate (PIDA) was developed. The protocol provides an efficient route for the synthesis of the alkaloids kealiinines B and C as well as homologues. The difference in the electronic nature of the acetylene substituent resulted in two ways of the cyclization. A plausible mechanism is proposed based on the experimental results.
- Tian, Guilong,Fedoseev, Pavel,Van der Eycken, Erik V.
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supporting information
p. 5224 - 5227
(2017/04/24)
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- Design and synthesis of neolamellarin a derivatives targeting heat shock protein 90
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In this study, we designed and synthesized a novel family of neolamellarin A derivatives that showed high inhibitory activity toward heat shock protein 90 (Hsp90), a kinase associated with cell proliferation. The 3,4-bis(catechol)pyrrole scaffold and the benzyl group with methoxy modification at N position of pyrrole are essential to the Hsp90 inhibitory activity and cytotoxicity of these compounds. Western blot analysis demonstrated that these compounds induced dramatic depletion of the examined client proteins of Hsp90, and accelerated cancer cell apoptosis. Docking simulations suggested that the binding mode of 9p was similar to that of the VER49009, a potent inhibitor of Hsp90. Further molecular dynamics simulation indicated that the hydrophobic interactions as well as the hydrogen bonds contributed to the high affinity of 9p to Hsp90.
- Jiang, Long,Yin, Ruijuan,Wang, Xueting,Dai, Jiajia,Li, Jing,Jiang, Tao,Yu, Rilei
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supporting information
p. 24 - 33
(2017/04/21)
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- Organocatalytic Enantioselective Pictet-Spengler Approach to Biologically Relevant 1-Benzyl-1,2,3,4-Tetrahydroisoquinoline Alkaloids
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(Figure Presented) A general procedure for the synthesis of 1-benzyl-1,2,3,4-tetrahydroisoquinolines was developed, based on organocatalytic, regio- and enantioselective Pictet-Spengler reactions (86-92% ee) of N-(o-nitrophenylsulfenyl)-2-arylethylamines with arylacetaldehydes. The presence of the o-nitrophenylsulfenyl group, together with the MOM-protection in the catechol part of the tetrahydroisoquinoline ring system, appeared to be a productive combination. To demonstrate the versatility of this approach, 10 biologically and pharmaceutically relevant alkaloids were prepared using (R)-TRIP as the chiral catalyst: (R)-norcoclaurine, (R)-coclaurine, (R)-norreticuline, (R)-reticuline, (R)-trimemetoquinol, (R)-armepavine, (R)-norprotosinomenine, (R)-protosinomenine, (R)-laudanosine, and (R)-5-methoxylaudanosine.
- Ruiz-Olalla, Andrea,Würdemann, Martien A.,Wanner, Martin J.,Ingemann, Steen,Van Maarseveen, Jan H.,Hiemstra, Henk
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p. 5125 - 5132
(2015/05/27)
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- Solvolysis, Electrochemistry, and Development of Synthetic Building Blocks from Sawdust
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Either aldehyde or cinnamyl ether products can be selectively extracted from raw sawdust by controlling the temperature and pressure of a solvolysis reaction. These materials have been used as platform chemicals for the synthesis of 15 different synthetic substrates. The conversion of the initial sawdust-derived materials into electron-rich aryl substrates often requires the use of oxidation and reduction chemistry, and the role electrochemistry can play as a sustainable method for these transformations has been defined.
- Nguyen, Bichlien H.,Perkins, Robert J.,Smith, Jake A.,Moeller, Kevin D.
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p. 11953 - 11962
(2016/01/09)
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- From (+)-epigallocatechin gallate to a simplified synthetic analogue as a cytoadherence inhibitor for P. falciparum
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Parasite derived surface antigen PfEMP1 is a virulence factor of the human malaria parasite. PfEMP1 variants have been implicated in the cytoadherence of P. falciparum infected erythrocytes (iRBC) to several binding receptors on host vascular endothelium. Among them, binding to ICAM-1 seems to be related to severe manifestations of the disease such as cerebral malaria. The binding site for iRBC has been mapped to the BED-side of the N-terminal immunoglobulin-like domain of ICAM-1, and the DE-loop appears to be critical for binding. To date (+)-EGCG is the unique small molecule anti-cytoadherence inhibitor probably mimicking the DE-loop of ICAM-1. Here we report the discovery of a tetrahydroisoquinoline derivative, a prototype of a novel class of cytoadherence inhibitors, and an analogue of the natural compound characterized by a synthetically accessible scaffold. Molecular modeling analysis of (+)-EGCG and its synthetic tetrahydroisoquinoline analogue rationalized their binding mode to PfEMP1, confirming their ability to mimic the DE-loop.
- Gemma, Sandra,Brogi, Simone,Patil, Pradeep R.,Giovani, Simone,Lamponi, Stefania,Cappelli, Andrea,Novellino, Ettore,Brown, Alan,Higgins, Matthew K.,Mustafa, Khairul,Szestak, Tadge,Craig, Alister G.,Campiani, Giuseppe,Butini, Stefania,Brindisi, Margherita
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p. 4769 - 4781
(2014/01/17)
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- A continuous flow solution to achieving efficient aerobic anti-Markovnikov Wacker oxidation
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An aerobic anti-Markovnikov Wacker oxidation for the flow-synthesis of arylacetaldehydes is reported. In the process, flow chemistry techniques have provided a means to control and minimise the over-oxidation of sensitive products. The reaction showed general applicability to various functionalised styrenes and provided a process capable of a multi-gram scale. Copyright
- Bourne,Ley
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supporting information
p. 1905 - 1910
(2013/08/23)
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- Design, synthesis, and biological evaluation of the first podophyllotoxin analogues as potential vascular-disrupting agents
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We designed and synthesized two novel series of azapodo-phyllotoxin analogues as potential antivascular agents. A linker was inserted between the trimethoxyphenyl ring E and the tetracyclic ABCD moiety of the 4-aza-1,2-didehydropodophyllotoxins. In the first series, the linker enables free rotation between the two moieties; in the second series, conformational restriction of the E nucleus was considered. We have identified several new compounds with inhibitory activity toward tubulin polymerization similar to that of CA-4 and colchicine, while displaying low cytotoxic activity against normal and/or cancer cells. An aminologue and a methylenic analogue were shown to disrupt endothelial cell cords on Matrigel at subtoxic concentrations, and an original assay of drug washout allowed us to demonstrate the rapid reversibility of this effect. These two new analogues are promising leads for the development of vascular-disrupting agents in the podophyllotoxin series.
- Labruere, Raphael,Gautier, Benoit,Testud, Marlene,Seguin, Johanne,Lenoir, Christine,Desbene-Finck, Stephanie,Helissey, Philippe,Garbay, Christiane,Chabot, Guy G.,Vidal, Michel,Giorgi-Renault, Sylviane
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p. 2016 - 2025
(2011/12/15)
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- Highly efficient ligands for dihydrofolate reductase from Cryptosporidium hominis and Toxoplasma gondii inspired by structural analysis
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The search for effective therapeutics for cryptosporidiosis and toxoplasmosis has led to the discovery of novel inhibitors of dihydrofolate reductase (DHFR) that possess high ligand efficiency: compounds with high potency and low molecular weight. Detaile
- Pelphrey, Phillip M.,Popov, Veljko M.,Joska, Tammy M.,Beierlein, Jennifer M.,Bolstad, Erin S. D.,Fillingham, Yale A.,Wright, Dennis L.,Anderson, Amy C.
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p. 940 - 950
(2007/10/03)
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- Synthesis of new 2,4-Diaminopyrido[2,3-d]pyrimidine and 2,4-Diaminopyrrolo[2,3-d]pyrimidine inhibitors of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductase
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A concise new route allowing easy access to five previously unreported 2,4-diamino-6-(substituted benzyl)pyrido[2,3-d]pyrimidines (2a-e) was developed, involving condensation of 2,4-dipivaloylamino-5-bromopyrido[2,3-d]pyrimidine (6) with an organozinc halide in the presence of a catalytic amount of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·CH 2Cl2, followed by removal of the pivaloyl groups with base. Also prepared via a scheme based on the Taylor ring expansion/ring annulation synthesis were three heretofore undescribed 2,4-diamino-5-(substituted benzyl)-7H-pyrrolo[2,3-d]pyrimidines (3b-c). Standard spectrophotometric assays were used to compare the ability of 2a-e and 3b-c to inhibit dihydrofolate reductase (DHFR) from Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium, three examples of opportunistic pathogens to which AIDS patients are highly vulnerable because of their immunocompromised state. For comparison, 13 previously untested 2,4-diamino-6-(substituted benzyl)quinazolines (17a-m) were also evaluated as inhibitors of these enzymes, as well as the enzyme from rat liver. None of the quinazolines or pyridopyrimidines tested was more potent against the P. carinii enzyme than the structurally related reference compound piritrexim (1), and none showed selectivity for the P. carinii enzyme over the rat enzyme. One of the pyridopyrimidines (2c) showed 10-fold selectivity for T. gondii versus rat DHFR, and two of them (2b, 2c) showed selectivity for the M. avium enzyme. However, this gain in species selectivity was achieved at the cost of decreased in potency, as has been noted with many other lipophilic DHFR inhibitors.
- Rosowsky, Andre,Chen, Han,Fu, Hongning,Queener, Sherry F.
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- Synthesis of Alkoxy-Substituted Diaryl Compounds and Correlation of Ring Separation with Inhibition of Tubulin Polymerization: Differential Enhancement of Inhibitory Effects under Suboptimal Polymerization Reaction Conditions
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A number of cytostatic compounds (2-4, 7, and 8), which can be described as "diaryl", inhibit tubulin polymerization, cause cells to accumulate in mitotic arrest, and competitively inhibit the binding of colchicine to tubuline.They differ, however, in the separation of the two aryl moieties.To attempt to understand this variability we prepared a series of analogues modeled on 3 and 4 ("benzodioxole series") and on 7 and 8 ("combretastatin series") which differed only in the number of methylene units (ranging from none to four) separating the aryl moieties.These compounds were evaluated for their effects on tubulin polymerization, colchicine binding, and the growth of L1210 murine leukemia cells.In terms of inhibitory effects on tubulin polymerization, for the combretastatin series there was an optimal separation of the two phenyl rings by a two-carbon bridge (compound 24), with progressively decreasing inhibitory activity when the separation was by one carbon (20), three carbons (25), or four carbons (28) (the biphenyl analogue 16 was inactive).The benzodioxole series, however, did not permit us to generalize this finding, because the least active agents prepared (39 and 40) had a two-carbon bridge, while those with one- (5 and 6) and three-carbon (46 and 47) bridges were nearly equivalent in potency.Submicromolar (IC50 values for inhibition of L1210 cell growth were only obtained for compounds 20 (IC50 0.2 μM), 24 (0.07 μM), and 25 (0.4 μM).While evaluating the effects of these agents on tubulin polymerization, we noted with the combretastatin series and with several standard agents that apparent potency (in terms of IC50 values) was always lower if the reaction was performed at 30 deg C, with 0.25 mM MgCl2, than at 37 deg C, with 1.0 mM MgCl2.This enhancement of IC50 values in the former system as compared with the latter was particularly dramatic for the less active agents (e.g., 28) as compared with the more active (e.g., 24).
- Getahun, Zelleka,Jurd, Leonard,Chu, Ping S.,Lin, Chii M.,Hamel, Ernest
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p. 1058 - 1067
(2007/10/02)
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- A Convenient Strategy for Homologation of p-Oxygenated Benzaldehydes
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It is shown that p-oxygenated benzaldehydes can be conveniently obtained by pyrolysis of the corresponding oxiranes.
- Haridas, K.,Dev, Sukh
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p. 1018 - 1020
(2007/10/02)
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