Discovery of certain benzyl/phenethyl thiazolidinone-indole hybrids as potential anti-proliferative agents: Synthesis, molecular modeling and tubulin polymerization inhibition study

Sigalapalli, Dilep Kumar; Pooladanda, Venkatesh; Singh, Priti; Kadagathur, Manasa; Guggilapu, Sravanthi Devi; Lakshmi, Uppu Jaya; Tangellamudi, Neelima D.; Reddy, Gangireddy Pavan Kumar; Godugu, Chandraiah; Babu, Bathini Nagendra

doi:10.1016/j.bioorg.2019.103188

Cited by 33 publications

(13 citation statements)

References 36 publications

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“…Disrupting the tubulin dynamics equilibrium blocks the cell division at mitosis and thus resulting in the cell cycle arrest at metaphase, which leads to cell death 6,7 . Moreover, cancer cells are more in the division phase than normal cells, which means that they are more prone to anti-tubulin agents 8 . Therefore, microtubules have become an attractive target for the design and development of novel anticancer agents [9][10][11] .…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of novel thiazole-naphthalene derivatives as potential anticancer agents and tubulin polymerisation inhibitors

Wang

Liu

Fan

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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A novel series of thiazole-naphthalene derivatives as tubulin polymerisation inhibitors were designed, synthesised, and evaluated for the anti-proliferative activities. The majority of the tested compounds exhibited moderate to potent antiproliferative activity on the MCF-7 and A549 cancer cell lines. Among them, compound 5b was found to be the most active compound with IC 50 values of 0.48 ± 0.03 and 0.97 ± 0.13 lM. Moreover, mechanistic studies revealed that 5b significantly inhibited tubulin polymerisation with an IC 50 value of 3.3 mM, as compared to the standard drug colchicine (IC 50 ¼ 9.1 lM). Further cellular mechanism studies elucidated that 5b arrested the cell cycle at G2/M phase and induced apoptosis in MCF-7 cancer cells. Molecular modelling study indicated that 5b binds well to the colchicine binding site of tubulin. In summary, these results suggest that 5b represents a promising tubulin polymerisation inhibitor worthy of further investigation as potential anticancer agents.

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Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of novel thiazole-naphthalene derivatives as potential anticancer agents and tubulin polymerisation inhibitors

Wang

Liu

Fan

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…When substrates 1a and 2a reacted in the deuterated [D 1 ]TFE solvent under optimized conditions, 68 % of deuterium was incorporated into one benzylic CH 2 group (Scheme ‐ 1). This result suggests that the protic solvent may transfer deuterium during the protodemetalation process . In addition, 100 % of deuterium incorporation in another ortho ‐position of phenyl was observed, which suggests that C–H activation step is reversible under the reaction conditions.…”

Section: Methodsmentioning

confidence: 91%

“…Considering the significance of C–H alkylation method with alkenes using cobalt catalyst, developing a general method without excess organometallic reagent that allows a wide range of simple arenes and alkenes is desirable. In particular, it would be interesting to develop cobalt‐catalyzed C(sp 2 )–H alkylations with styrenes to provide phenylethylene groups, which are often found in biologically active compounds . On the basis of our interest in Cp*Co III ‐catalyzed C–H bond activations, we report herein a straightforward method for linear‐selective C(sp 2 )–H alkylation with styrene derivatives (Scheme C).…”

Section: Methodsmentioning

confidence: 99%

Cobalt‐Catalyzed Direct C(sp²)–H Alkylation with Unactivated Alkenes

2020

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A facile and efficient method for Cp*CoIII‐catalyzed C(sp2)–H bond alkylation was developed using 2‐aryl pyridines and unactivated alkenes. The reaction proceeded atom‐economically with readily available styrene derivatives and an abundant cobalt catalyst. This reaction tolerates a broad range of functional groups, directing groups, styrenes and affords mono‐diarylethane products with high linear selectivity. To demonstrate the synthetic utility and the potential application in organic synthesis, a gram‐scale reaction and further C–H bond functionalizations of the mono‐alkylated product were performed.

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“…Many indole derivatives induce apoptosis via inhibition of tubulin polymerization in cancer chemotherapy (Brancale & Silvestri, 2007). Some examples are 2‐phenylindole ( V ), 2‐aroylindole ( VI ), and indolyl‐3‐glyoxamide ( VII ) compounds (Sigalapalli et al, 2019). Also, indole containing compounds VIII & IX were reported to have both potent antitubulin and antitumor activities (Álvarez et al, 2013; Álvarez et al, 2018; Yan et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, biological evaluation, and molecular docking of new benzofuran and indole derivatives as tubulin polymerization inhibitors

El‐Sayed

El‐Hussieny

Ewies

et al. 2021

Drug Development Research

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Microtubules and the mitotic spindle have become an important target for cancer treatment due to their critical role in cell division. In this work, a novel series of benzofuran and indole derivatives were designed and synthesized, to be evaluated as tubulin polymerization inhibitors. 2‐Acetylbenzofuran derivatives 1a,b and 3‐acetylindole 1c were condensed with Wittig reagents 2a–d and Wittig‐Horner reagents 3a–e to afford the respective 2‐ethylidene derivatives 5a–j and 7a–e. Also, iminomethylene triphenylphosphine (2e) reacted with 1a,b to afford benzofuran‐2‐ylethylidene aniline derivatives 6a,b. In addition, compounds 1a,b reacted with trialkylphosphites 4a–c to give 1:1 adduct for which the Oxaphospholo[4,3‐b]benzofuran‐7‐yl)diazene derivatives 8a–f, were assigned. The possible reactions mechanisms were discussed and structural reasoning for the new compounds were based upon spectroscopic data. Their antiproliferative activities against two cell lines namely, HepG2 and MCF7 cells were then evaluated. It was found that the benzofuran compounds 5b, 6a, and 8c exhibited the strongest antiproliferative activities against both cell lines compared to doxorubicin. By studying the mechanism of action, compound 6a showed good inhibition of tubulin polymerization which leads to mitotic spindle formation disruption, cell cycle arrest in the G2/M phase, and apoptosis of HepG2 cells. A conducted docking study confirmed the in vitro results indicating that compound 6a fitted properly at the colchicine binding site of tubulin. Based on these findings, compound 6a can be considered as a promising anticancer candidate that can be subjected for further development as a tubulin polymerization inhibitor for treating liver and breast cell carcinoma.

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Discovery of certain benzyl/phenethyl thiazolidinone-indole hybrids as potential anti-proliferative agents: Synthesis, molecular modeling and tubulin polymerization inhibition study

Cited by 33 publications

References 36 publications

Design, synthesis and biological evaluation of novel thiazole-naphthalene derivatives as potential anticancer agents and tubulin polymerisation inhibitors

Design, synthesis and biological evaluation of novel thiazole-naphthalene derivatives as potential anticancer agents and tubulin polymerisation inhibitors

Cobalt‐Catalyzed Direct C(sp²)–H Alkylation with Unactivated Alkenes

Design, synthesis, biological evaluation, and molecular docking of new benzofuran and indole derivatives as tubulin polymerization inhibitors

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Discovery of certain benzyl/phenethyl thiazolidinone-indole hybrids as potential anti-proliferative agents: Synthesis, molecular modeling and tubulin polymerization inhibition study

Cited by 33 publications

References 36 publications

Design, synthesis and biological evaluation of novel thiazole-naphthalene derivatives as potential anticancer agents and tubulin polymerisation inhibitors

Design, synthesis and biological evaluation of novel thiazole-naphthalene derivatives as potential anticancer agents and tubulin polymerisation inhibitors

Cobalt‐Catalyzed Direct C(sp2)–H Alkylation with Unactivated Alkenes

Design, synthesis, biological evaluation, and molecular docking of new benzofuran and indole derivatives as tubulin polymerization inhibitors

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Cobalt‐Catalyzed Direct C(sp²)–H Alkylation with Unactivated Alkenes