Exploring Pyrrolo-Fused Heterocycles as Promising Anticancer Agents: An Integrated Synthetic, Biological, and Computational Approach

Abstract

Five new series of pyrrolo-fused heterocycles were designed through a scaffold hybridization strategy as analogs of the well-known microtubule inhibitor phenstatin. Compounds were synthesized using the 1,3-dipolar cycloaddition of cycloimmonium N-ylides to ethyl propiolate as a key step. Selected compounds were then evaluated for anticancer activity and ability to inhibit tubulin polymerization in vitro. Notably, pyrrolo[1,2-a]quinoline 10a was active on most tested cell lines, performing better than control phenstatin in several cases, most notably on renal cancer cell line A498 (GI50 27 nM), while inhibiting tubulin polymerization in vitro. In addition, this compound was predicted to have a promising ADMET profile. The molecular details of the interaction between compound 10a and tubulin were investigated through in silico docking experiments, followed by molecular dynamics simulations and configurational entropy calculations. Of note, we found that some of the initially predicted interactions from docking experiments were not stable during molecular dynamics simulations, but that configurational entropy loss was similar in all three cases. Our results suggest that for compound 10a, docking experiments alone are not sufficient for the adequate description of interaction details in terms of target binding, which makes subsequent scaffold optimization more difficult and ultimately hinders drug design. Taken together, these results could help shape novel potent antiproliferative compounds with pyrrolo-fused heterocyclic cores, especially from an in silico methodological perspective.

Norcantharidin Enhances the Antitumor Effect of 5-Fluorouracil by Inducing Apoptosis of Cervical Cancer Cells: Network Pharmacology, Molecular Docking, and Experimental Validation

“…These hydrogen bond interactions may provide the fundamental conditions for the reaction of caspase-9 with NCTD and 5-FU. Furthermore, we performed molecular dynamics simulations of both complexes for up to 10 ns [37], which revealed that both small molecules can form hydrogen bonds with caspase-9 (Figure S1D). Hydrogen bonding is a very strong non-covalent interaction that can reflect, to some extent, the binding strength between the ligand and the receptor.…”

In Vitro and In Silico Evaluation of Antiproliferative Activity of New Isoxazolidine Derivatives Targeting EGFR: Design, Synthesis, Cell Cycle Analysis, and Apoptotic Inducers

“…As a result, the trend of the RGyr plot versus simulation time and its low fluctuation surely explain the residual backbone and how folding of the EGFR protein remained stable after interaction with compounds 2f and 2g. [35][36][37][38][39][40][41] An in silico study (Table 4) of the most biologically active synthesized compounds 2f and 2g has been assessed by Swiss ADME server. Lipinski's rule states that both investigated molecules satisfied this rule and thereby should be taken orally.…”

“…Our findings revealed that 2f and 2g could be good templates for further drug discovery and development. [35][36][37][38][39][40][41] An in silico study (Table 4) of the most biologically active synthesized compounds 2f and 2g has been assessed by Swiss ADME server. Lipinski's rule states that both investigated molecules satisfied this rule and thereby should be taken orally.…”

New monoquaternary salts of N-heterocycles: synthesis and antitumor assessment

“…Given the information discussed above, the focus of our current study is to synthesize new derivatives, building upon our previous research on N-heterocycle systems, [12][13][14] while remaining aligned with our keen interest in exploring chemical compounds with physiological activity. [15][16][17][18][19] This article presents our findings, including the synthesis, characterization, and antitumor evalution of several new N-heterocycle monoquaternary salts. Additionaly, we discuss two unexpected physical mixtures that formed during the process (Fig.…”