Conjugate Addition of Amines to Sugar Derived Olefinic Esters: Synthesis of Glycosylated Amino Esters as Dna Topoisomerase-Ii Inhibitors

Khan, Abdul Rahman; Tripathi, Rama Pati; Tiwari, Vinod K.; Mishra, Rupesh K.; Reddy, Venkata Jaganmohan; Saxena, Jitendra Kumar

doi:10.1081/car-120016857

Cited by 28 publications

(12 citation statements)

References 8 publications

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“…In a parasitic context it is especially important to consider their function in the regulation of the oxidative stress response, in drug resistance and possibly in the modulation of host immune defence mechanisms. In ongoing research programmes towards the development of biologically active compounds from sugars, glycosylated amino acid derivatives have been shown to possess various biological activities including parasitic DNA topoisomerase-II, as well as glutathione-S-transferase inhibitory, antitubercular and immunomodulatory activities [25,27,48,49]. Recognition of certain glycosylated amino acid derivatives by merozoites of the malarial parasite [50], which divide in the red blood cells of the host, has also been reported.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and biological evaluation of potential modulators of malarial glutathione-S-transferase(s)

Ahmad

Srivastava

Tripathi

et al. 2007

Journal of Enzyme Inhibition and Medicinal Chemistry

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Glutathione-S-transferase(s) (E.C.2.5.1.18, GSTs) have been investigated in parasitic protozoans with respect to their biochemistry and they have been identified as potential vaccine candidates in protozoan parasites and as a target in the synthesis of new antiparasitic agents. In a search towards the identification of novel biochemical targets for antimalarial drug design, the area of Plasmodium glutathione metabolism provides a number of promising chemotherapeutic targets. GST activity was determined in various subcellular fractions of malarial parasites Plasmodium yoelii and was found to be localized mainly in the cytosolic fraction (specific activity, c. 0.058^0.016 mmol/min/mg protein). Hemin, a known inhibitor of mammalian GST(s), maximally inhibited this enzyme from P. yoelii to nearly 86%. In a search towards synthetic modulators of malarial GST(s), 575 compounds belonging to various chemical classes were screened for their effect on crude GST from P. yoelii and 92 compounds belonging to various chemical classes were studied on recombinant GST from P. falciparum. Among all the compounds screened, 83 compounds inhibited/stimulated the enzyme from P. yoelii/P. falciparum to the extent of 40% or more.

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Section: Discussionmentioning

confidence: 99%

Synthesis and biological evaluation of potential modulators of malarial glutathione-S-transferase(s)

Ahmad

Srivastava

Tripathi

et al. 2007

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Compounds B and C were synthesized by a procedure already reported by us (Khan et al 2002;Mishra-Bhattacharya et al 2004) and identical in all respects to the earlier reported compounds. Compound A was a newly synthesized compound and its synthetic protocol and physical data are given in the experimental section.…”

Section: Compounds and Their Synthesismentioning

confidence: 99%

Search for new prototypes for the chemotherapy of filariasis: a chemotherapeutic and biochemical approach

et al. 2005

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The antifilarial activity of two coumarin derivatives (A, B) and three glycosyl amine derivatives (D, E, F) was evaluated against a subperiodic strain of human lymphatic filarial parasite Brugia malayi by the intraperitoneal route at 50 mg/kg for 5 consecutive days. Of these, the two sugar derivatives (D and E) were selected for evaluation by the oral route based on their microfilaricidal (mild), macrofilaricidal and female worm sterilization efficacy using the i.p. route of administration. Compound E was finally selected for combination therapy on the basis of its microfilaricidal and embryostatic action by the oral route and its spectrum of activity against micro- and macrofilariae including embryostatic activity by the i.p. route. In addition, E also significantly inhibited the parasite DNA topoisomerase II. Compound A, in contrast, led to an enhanced adult worm burden. Compound B was toxic by the i.p. route, killing all of the treated animals before completion of the experiment. Some of these compounds demonstrated significant antifilarial efficacy of varying degree when tested in vitro Compounds B, D and F also killed adult B. malayi in vitro at 100 muM while 50 muM resulted in very slow motility of worms. Compound E in combination with a promising macrofilaricidal benzopyran derivative reported by us recently (compound C) did not show any synergistic or additive effect. These two compounds (C and E) individually on oral administration with either DEC or ivermectin significantly improved microfilaricidal efficacy in terms of intensity and duration of suppressed microfilaraemia. The combination of DEC with compound E demonstrated marginal enhancement in adulticidal efficacy, however, the embryostatic effect of the duo was significantly higher than that exerted by the individual agents. It may thus be inferred that in the absence of an adulticidal antifilarial drug, the use of potential antifilarials in combination with the standard filaricides may yield better results.

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“…Michael addition has been used for piperidine ring formation and for the asymmetric synthesis of β-amino esters [129][130][131][132][133]. The intra-and intermolecular addition of a nucleophilic amine to α,β-unsaturated ester can be stereoselective due to the substrate auxiliary.…”

Section: Aza-c-glycosides By a Hetero-michael Additionmentioning

confidence: 99%

C-Glycosides and Aza-C-Glycosides as Potential Glycosidase and Glycosyltransferase Inhibitors

Zou¹

2005

CTMC

146

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Glycosylation as one of most important post-translational modification of gene products is often critical to specific cellular biological functions. Since elevated glycoprocessing enzyme activities have been implicated in the development of various diseases including cancer metastasis, glycosidases and glycosyltransferases are considered as therapeutic targets. Azasugars, the first generation of enzyme inhibitors, have been extensively investigated and two azasugar-based drugs (Miglitol and Miglustat) have been approved. Aza-C-glycosides, molecules with an azasugar core and various C-aglycons attached at the pseudo anomeric center, have the potential to become the second-generation inhibitors with improved specificity and membrane permeability. In this review, C-glycosides, aza-C-glycosides, and aza-C-disaccharides are introduced as glycoprocessing enzyme inhibitors. The synthetic approaches toward those molecules are described based on the key reactions, which include reductive amination, nucleophilic ring opening of epoxides, nucleophilic addition to imines (C=N), and hetero-Michael additions. Aza-C-glycoside-based libraries are also described for the discovery of promising second-generation inhibitors.

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Conjugate Addition of Amines to Sugar Derived Olefinic Esters: Synthesis of Glycosylated Amino Esters as Dna Topoisomerase-Ii Inhibitors

Abstract: Conjugate addition of amines to olefinic esters derived from sugars leading to formation of glycosylated amino esters in a stereoselective manner is described. Some of the synthesized compounds possess DNA topoisomerase-II enzyme inhibitory activities at low concentrations.

Cited by 28 publications

References 8 publications

Synthesis and biological evaluation of potential modulators of malarial glutathione-S-transferase(s)

Synthesis and biological evaluation of potential modulators of malarial glutathione-S-transferase(s)

Search for new prototypes for the chemotherapy of filariasis: a chemotherapeutic and biochemical approach

C-Glycosides and Aza-C-Glycosides as Potential Glycosidase and Glycosyltransferase Inhibitors

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