Pyrazole–oxadiazole conjugates: synthesis, antiproliferative activity and inhibition of tubulin polymerization

Abstract

A number of pyrazole-oxadiazole conjugates were synthesized and evaluated for their ability to function as antiproliferative agents on various human cancer cell lines. These conjugates are comprised of pyrazole and oxadiazole scaffolds closely attached to each other without any spacer as two structural classes. The Type I class has a trimethoxy substituent and the type II class has a 3,4-(methylenedioxy) substituent on their A rings. Among these conjugates 11a, 11d and 11f manifest potent cytotoxicity with IC50 values ranging from 1.5 μM to 11.2 μM and inhibit tubulin polymerization with IC50 values of 1.3 μM, 3.9 μM and 2.4 μM respectively. The cell cycle assay showed that treatment with these conjugates results in accumulation of cells in the G2/M phase and disrupts the microtubule network. Elucidation of zebrafish embryos revealed that the conjugates cause developmental defects. Molecular docking simulations determined the binding modes of these potent conjugates at the colchicine site of tubulin.

Design and synthesis of pyrazole/isoxazole linked arylcinnamides as tubulin polymerization inhibitors and potential antiproliferative agents

“…These were oxidized to the pyrazole carbaldehydes (11a-d) by using IBX in DMSO. 24 These pyrazole carbaldehydes upon reaction with (carbethoxymethylene)triphenylphosphine, Ph 3 PCHCO 2 C 2 H 5 (C2-Wittig salt) in toluene afforded α,β-unsaturated esters 12a-d that subsequently underwent a base hydrolysis to give α,β-unsaturated carboxylic acids 13a-d. 26,27 Finally, these carboxylic acids conveniently coupled with substituted arylamines 14a-d in the presence of EDC/ Hobt produce the desired pyrazole linked phenylcinnamides (PP). 19 By employing the same methodology isoxazole linked (1), combretastatin-A4 (2), nocodazole (3), phenylcinnamides (4), thiadiazole ring based cinnamide (5), acrylylpiperazine (6) phenylcinnamide conjugates 21a-n were synthesized starting from isoxazole esters (16a-d) as shown in Scheme 2.…”

“…[21][22][23] Previously we have reported that a series of pyrazole based conjugates have shown profound cytotoxic effects by arresting the cells in the G2/M phase. [24][25][26] In view of the attractive biological activities exhibited by them, considerable interest in the development of newer cytotoxic agents has been aroused. The present work illustrates the design and synthesis of some pyrazole/isoxazole linked arylcinnamide conjugates and evaluates their ability to inhibit the growth of a panel of four human cancer cell lines.…”

One‐Pot Synthesis of Hydroxy Pyrazolo[1,2‐a][1,2,4]triazoles and Their Dehydration Using Recyclable Ionic Liquids as Reaction Media

“…Silica gel 60 A mixture of aldehyde I (1.0 mmol), 4-phenylurazole (1.0 mmol) and ethyl/methyl acetoacetate II (1.0 mmol), 3 mL of [bmim]BF 4 , and L-proline (10 mol%) was placed in a 50-mLround-bottomed flask. The reaction contents were stirred magnetically in an oil bath maintained at 80°C for appropriate time as mentioned in Table 2.…”

“…triazole-6-carboxylate (IIIa) [17] 4 . Operational simplicity, lesser reaction time, high yields of products, and recyclability of catalyst and ionic liquids are the conspicuous advantages of the present protocol.…”

“…Heterocycles containing pyrazole scaffolds are known to exhibit an extensive range of biological activities, such as analgesic, antipyretic, antiinflammatory, antioxidant, antibacterial, and anticancer activities [1][2][3][4]. Pyrazole-based compounds are reported to exert their anticancer activity through inhibition of various targets such as epidermal growth factor, tumor growth factor, fibroblast growth factor, telomerase, and different kinases that are significant for the management of cancer [5][6][7].…”