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. 2025 Jul 2;16(10):4845-4858.
doi: 10.1039/d5md00406c. eCollection 2025 Oct 15.

Microwave-assisted synthesis of tubulin assembly inhibitors as anticancer agents by aryl ring reversal and conjunctive approach

Domiziana Masci  1   2 , Michela Puxeddu  3 , Claudia Colla  3 , Antonio Coluccia  3 , Martina Santelli  1 , Pietro Sciò  3 , Elena Mariotto  4   5 , Giampietro Viola  4   5 , Ernest Hamel  6 , Rosa Lerose  7 , Carmela Mazzoccoli  7 , Romano Silvestri  3 , Giuseppe La Regina  3
Affiliations

Microwave-assisted synthesis of tubulin assembly inhibitors as anticancer agents by aryl ring reversal and conjunctive approach

Domiziana Masci et al. RSC Med Chem. .

Abstract

Microwave-assisted synthesis of new pyrrole and indole derivatives as tubulin assembly inhibitors was performed with remarkably improved yields and short reaction times. In designing the new inhibitors, aryl ring reversal and conjunctive approach notions were applied. (4-(4-Methoxyphenyl)-1-(pyridin-2-yl)-1H-pyrrol-3-yl)(3,4,5-trimethoxyphenyl) methanone (4) inhibited [3H] colchicine binding by 78% and MCF-7 breast cancer cell growth with an IC50 of 9.6 nM. Compound 4 also inhibited the growth of HCT116, BX-PC3 and Jurkat cancer cells with IC50 values of 18, 17 and 41 nM, respectively, and altered the morphology of treated spheroids in both the BX-PC3 and HCT116 cell lines.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Chart 1
Chart 1. General structures: reference compounds 1 and 2, new pyrrole 3–24 and indole 25–30 derivatives. See Tables 1 and 2 for R1 and R2 values.
Scheme 1
Scheme 1. Reagents and conditions: (a) appropriate halogenated-pyridine or pyrimidine, CuI, Cs2CO3, 1,10-phenanthroline, dry 1,4-dioxane, MW irradiation, (closed vessel, 150 W, 180 °C, 40 min), yield: 22–89%. R1: see Table 1. X: 31, 4-methyl; 32, 4-methoxy; 33, 4-trifluoromethyl; 34: 4-chloro; 35: 4-N,N-dimethylamino; 36: 3,5-dimethoxy; 37: 3,4,5-trimethoxy; 38: 4-fluoro; 39: 4-nitro; 40: R2 = (E)-4-styryl: 4-(piperidin-1-yl).
Scheme 2
Scheme 2. Reagents and conditions: (a) 3,4,5-trimethoxybenzoyl chloride, AlCl3, 1,2-dichloroethane, MW irradiation (closed vessel, 150 W, 110 °C, 4 min), yield: 41–96%; (b) 2-bromopyridine, 3-bromopyridine or 2-bromopyrimidine, CuI, Cs2CO3, 1,10-phenanthroline, dry 1,4-dioxane, MW irradiation (closed vessel, 150 W, 180 °C, 40 min), yield: 29–81%. R1: see Table 2. R2: 42, 46: Cl; 43, 47: F; 44, 48: CN; 45, 49: OMe.
Chart 2
Chart 2. SAR summary of MCF-7 cell growth inhibition: +, weak; ++ strong; +++ strongest; −, no data. See Charts 1 and 2 for structural formulas 3–24 and 25–30.
Fig. 1
Fig. 1. Effect of 4 on 3D culture from BX-PC3 and HCT116 cells. (A) Representative images of 3D culture obtained from BX-PC3 seeded into ultra-low attachment plates, cultured for 7 days to obtain spheroids and treated with 320 nM 4 for 48 h. Spheroid diameter measurement was obtained with Zen software in BX-PC3 cells. (B) Representative images of 3D culture obtained from HCT116 cells seeded into ultra-low attachment plates, cultured for 7 days to obtain spheroids and treated with 160 nM 4 for 48 h. Spheroid diameter measurement at 160 nM was obtained with Zen software. Bars are averaged normalized values ± SD of three independent experiments: (*) p < 0.05.
Fig. 2
Fig. 2. Proposed binding mode for compound 4. Protein is depicted as a cartoon, orange for β- and light blue for α-subunits. Residue involved in interactions are depicted as grey lines.
See this image and copyright information in PMC

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