Recent Trends in Tubulin-Binding Combretastatin A-4 Analogs for Anticancer Drug Development.

Although significant progress over several decades has been evidenced in cancer therapy, there remains a need for the development of novel and effective therapeutic strategies to treat several relapsed and intractable cancers. In this regard, tubulin protein has become one of the efficient and major targets for anticancer drug discovery. Considering the antimitotic ability, several tubulin inhibitors have been developed to act against various cancers. Among various tubulin inhibitors available, combretastatin-A4 (CA-4), a naturally occurring lead molecule, offers exceptional cytotoxicity (including the drugresistant cell lines) and antivascular effects. Although CA-4 offers exceptional therapeutic efficacy, several new advancements have been proposed, in terms of structural modification via A and B rings, as well as cis-olefinic bridging, which provide highly efficient analogs with improved tubulin-binding efficiency to meet the anticancer drug development requirements. This review systematically emphasizes the recent trends and latest developments in the anticancer drug design and discovery using CA-4 analogs as the tubulin inhibiting agents by highlighting their structure-activity relationships (SAR) and resultant pharmacological efficacies.

Synthesis of podophyllotoxin-glycosyl triazoles via click protocol mediated by silver (I)-N-heterocyclic carbenes and their anticancer evaluation as topoisomerase-II inhibitors.

Herein we report the regioselective synthesis of podophyllotoxin-Glycosyl triazole hybrids catalysed by Ag(I)-N-heterocyclic carbene (Ag(I)-NHC) in a short reaction time (∼30 min) at ambient conditions. In principle, it is the first report of Click alkyne-azide cycloaddition catalysed by Ag(I)-NHC catalyst and moreover, this new methodology yielded good results when compared with traditional CuAAC in terms of reaction time and selectivity. The synthesised compounds were further explored for in vitro anticancer activity against four human cancer cell lines Du145, HeLa, A-549, and MCF-7 and found that these synthesised compounds possess significant anticancer activity. Further, the compounds 5a and 5e were identified as promising leads due to their better activity across all cell lines than that of the standard drug etoposide. Molecular docking studies of 5a & 5e with DNA Topoisomerase-II were revealed that the free energy calculations of active compounds were in good agreement with observed IC50 values.

Synthesis of d-ring modified acid hydrazide derivatives of podophyllotoxin and their anticancer studies as Tubulin inhibiting agents.

A new series (except compound 3a) of d-ring modified acid hydrazides of podophyllotoxin were synthesized by cleaving of its d-ring with various hydrazines. Furthermore, the synthesized compounds were screened for their anticancer activity against human tumor cell lines i.e., MCF-7, HeLa and A-549 and among the synthesized compounds 3c and 3f have shown significant anticancer activity almost similar to that of standard drug etoposide. Molecular modelling studies were also conducted for active compounds and found that the free energies obtained were in good agreement with the observed IC50 values.

Design and synthesis of 4ß-Acetamidobenzofuranone-podophyllotoxin hybrids and their anti-cancer evaluation.

A new series of amide derivatives of 4ß-Acetamidobenzofuranone-podophyllotoxin hybrids (14a-g) were synthesized and their chemical structures were confirmed by 1H, 13C NMR and mass spectral data. Further, all the synthesized Acetamidobenzofuranone-podophyllotoxin hybrids were evaluated for in vitro cytotoxic activity against a panel of four human cancer cell lines i.e., human breast (MCF-7, MDA MB-231), lung (A549), and prostrate (DU-145). Among benzofuranone-podophyllotoxin hybrid compounds, 14b and 14e were exhibited more potent activity than standard drug and 14c and 14f were showed anticancer activity equivalent to etoposide.

Regioselective synthesis of isoxazole-mercaptobenzimidazole hybrids and their in vivo analgesic and anti-inflammatory activity studies.

Regioselective synthesis of isoxazole-mercaptobenzimidazole hybrids and their efficiency in in vivo analgesic and anti-inflammatory activity was described. A comparison of structure-activity relationship for there compounds was also emphasized.