Rational design of biaryl pharmacophore inserted noscapine derivatives as potent tubulin binding anticancer agents

Abstract

We have strategically designed a series of noscapine derivatives by inserting biaryl pharmacophore (a major structural constituent of many of the microtubule-targeting natural anticancer compounds) onto the scaffold structure of noscapine. Molecular interaction of these derivatives with α,β-tubulin heterodimer was investigated by molecular docking, molecular dynamics simulation, and binding free energy calculation. The predictive binding affinity indicates that the newly designed noscapinoids bind to tubulin with a greater affinity. The predictive binding free energy (ΔG(bind, pred)) of these derivatives (ranging from -5.568 to -5.970 kcal/mol) based on linear interaction energy (LIE) method with a surface generalized Born (SGB) continuum solvation model showed improved binding affinity with tubulin compared to the lead compound, natural α-noscapine (-5.505 kcal/mol). Guided by the computational findings, these new biaryl type α-noscapine congeners were synthesized from 9-bromo-α-noscapine using optimized Suzuki reaction conditions for further experimental evaluation. The derivatives showed improved inhibition of the proliferation of human breast cancer cells (MCF-7), human cervical cancer cells (HeLa) and human lung adenocarcinoma cells (A549), compared to natural noscapine. The cell cycle analysis in MCF-7 further revealed that these compounds alter the cell cycle profile and cause mitotic arrest at G2/M phase more strongly than noscapine. Tubulin binding assay revealed higher binding affinity to tubulin, as suggested by dissociation constant (Kd) of 126 ± 5.0 µM for 5a, 107 ± 5.0 µM for 5c, 70 ± 4.0 µM for 5d, and 68 ± 6.0 µM for 5e compared to noscapine (Kd of 152 ± 1.0 µM). In fact, the experimentally determined value of ΔG(bind, expt) (calculated from the Kd value) are consistent with the predicted value of ΔG(bind, pred) calculated based on LIE-SGB. Based on these results, one of the derivative 5e of this series was used for further toxicological evaluation. Treatment of mice with a daily dose of 300 mg/kg and a single dose of 600 mg/kg indicates that the compound does not induce detectable pathological abnormalities in normal tissues. Also there were no significant differences in hematological parameters between the treated and untreated groups. Hence, the newly designed noscapinoid, 5e is an orally bioavailable, safe and effective anticancer agent with a potential for the treatment of cancer and might be a candidate for clinical evaluation.

Bioengineering of Anti‐Inflammatory Natural Products

“…The biosynthesis of noscapine ( 5 ) starts from l ‐tyrosine ( 6 ) and proceeds via the intermediate reticuline ( 7 ). Residues that were successfully modified in reticuline and noscapine by biotechnological or semisynthetic methods are highlighted [90–102,105,106,108] …”

The Noscapine Chronicle: A Pharmaco‐Historic Biography of the Opiate Alkaloid Family and its Clinical Applications

“…Multiple studies have been conducted synthesizing and evaluating novel biaryl type α‐noscapine congeners where an aryl unit is added to the tetrahydroisoquinoline of the natural α‐noscapine core, the scaffold structure of noscapine. Through palladium catalyzed Suzuki cross‐couplings of 9‐bromo α‐noscapine with aryl boronic acids, multiple noscapinoids were recovered and three were found to have potent cytotoxic and tubulin‐binding activity against human breast epithelial (MCF‐7), human cervical cancer (HeLa), and human lung adenocarcinoma epithelial (A549) cell lines …”

“…Through palladium catalyzed Suzuki cross-couplings of 9-bromo α-noscapine with aryl boronic acids, multiple noscapinoids were recovered and three were found to have potent cytotoxic and tubulin-binding activity against human breast epithelial (MCF-7), human cervical cancer (HeLa), and human lung adenocarcinoma epithelial (A549) cell lines. 95,97…”

Synthesis of novel aryl dithian valeryl podophyllotoxin ester derivatives as potential antitubulin agents

“…1,2 Microtubules are long, hollow, cylindrical polymers composed of aand b-tubulin dimers. 6,7 Disruption of microtubule dynamics or formation of abnormal mitotic microtubules prevents rearrangement of the microtubule network, which can induce cell cycle arrest in G2/M phase and trigger cells death. 6,7 Disruption of microtubule dynamics or formation of abnormal mitotic microtubules prevents rearrangement of the microtubule network, which can induce cell cycle arrest in G2/M phase and trigger cells death.…”

“…1), a naturally occurring cyclolignan which is the main component of podophyllum resin, exhibits pronounced biological activities, especially anticancer effects through inhibiting microtubule assembly. [13][14][15][16][17] Herein, we have to note some well-known drugs, GL331 (2), NPF (3), TOP53 (4), and NK611 (5), especially the three most highly prescribed anticancer drugs in the world, etoposide (6), teniposide (7), and the water-soluble prodrug etopophos (8), that base on podophyllotoxin scaffold. [13][14][15][16][17] Herein, we have to note some well-known drugs, GL331 (2), NPF (3), TOP53 (4), and NK611 (5), especially the three most highly prescribed anticancer drugs in the world, etoposide (6), teniposide (7), and the water-soluble prodrug etopophos (8), that base on podophyllotoxin scaffold.…”