Regioselective Approach to Colchiceine Tropolone Ring Functionalization at C(9) and C(10) Yielding New Anticancer Hybrid Derivatives Containing Heterocyclic Structural Motifs

Overview

Journal J Enzyme Inhib Med Chem

Specialty Biochemistry

Date 2022 Jan 24

PMID 35067138

Authors

Krystian Pyta

Natalia Skrzypczak

Piotr Ruszkowski

Franz Bartl

Piotr Przybylski

Affiliations

Soon will be listed here.

Abstract

The influence of base type, temperature, and solvent on regioselective C(9)/C(10) "" modifications within the tropolone ring of colchiceine () is investigated. New ether derivatives of , bearing alkyne, azide, vinyl, or halide aryl groups enable assembly of the alkaloid part with heterocycles or important biomolecules such as saccharides, geldanamycin or AZT into hybrid scaffolds by dipolar cycloaddition (CuAAC) or Heck reaction. Compared to colchicine () or colchiceine (), ether congeners, as e.g. [ICs ∼ 0.9 nM], show improved or similar anticancer effects, whereby the bulkiness of the substituents and the substitution pattern of the tropolone proved to be essential. Biological studies reveal that expanding the ether arms by terminal basic heterocycles as quinoline or pyridine, decreases the toxicity in HDF cells at high anticancer potency (ICs ∼ 1-2 nM). Docking of ether and hybrid derivatives into the colchicine pocket of α/β tubulin dimers reveals a relationship between the favourable binding mode and the attractive anticancer potency.

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References

Bonandi E, Foschi F, Marucci C, Dapiaggi F, Sironi M, Pieraccini S . Synthesis of Thicolchicine-Based Conjugates: Investigation towards Bivalent Tubulin/Microtubules Binders. Chempluschem. 2020; 84(1):98-102. DOI: 10.1002/cplu.201800497. View

Thomopoulou P, Sachs J, Teusch N, Mariappan A, Gopalakrishnan J, Schmalz H . New Colchicine-Derived Triazoles and Their Influence on Cytotoxicity and Microtubule Morphology. ACS Med Chem Lett. 2016; 7(2):188-91. PMC: 4753549. DOI: 10.1021/acsmedchemlett.5b00418. View

Sharma N, Mohanakrishnan D, Shard A, Sharma A, Saima , Sinha A . Stilbene-chalcone hybrids: design, synthesis, and evaluation as a new class of antimalarial scaffolds that trigger cell death through stage specific apoptosis. J Med Chem. 2011; 55(1):297-311. DOI: 10.1021/jm201216y. View

Shaala L, Youssef D . Identification and bioactivity of compounds from the fungus Penicillium sp. CYE-87 isolated from a marine tunicate. Mar Drugs. 2015; 13(4):1698-709. PMC: 4413182. DOI: 10.3390/md13041698. View

Ghawanmeh A, Al-Bajalan H, Mackeen M, Alali F, Chong K . Recent developments on (-)-colchicine derivatives: Synthesis and structure-activity relationship. Eur J Med Chem. 2019; 185:111788. DOI: 10.1016/j.ejmech.2019.111788. View

Cavazza M, Pietra F . Tautomeric selectivity towards colchicinoids in the tosylation of colchiceine on a heterogeneous, easily removable catalyst. Org Biomol Chem. 2003; 1(17):3002-3. DOI: 10.1039/b307650b. View

Bagnato J, Eilers A, Horton R, Grissom C . Synthesis and characterization of a cobalamin-colchicine conjugate as a novel tumor-targeted cytotoxin. J Org Chem. 2004; 69(26):8987-96. DOI: 10.1021/jo049953w. View

Wang X, Sun H, Liu J, Zhong W, Zhang M, Zhou H . Palladium-Promoted DNA-Compatible Heck Reaction. Org Lett. 2019; 21(3):719-723. DOI: 10.1021/acs.orglett.8b03926. View

Carreno M, Ortega-Guerra M, Ribagorda M, Sanz-Cuesta M . Synthesis of 4-aminotropones from [(sulfinyl or sulfonyl)methyl]-substituted p-quinamines. Chemistry. 2007; 14(2):621-36. DOI: 10.1002/chem.200700940. View

10.

Trost B, McDougall P . Access to a welwitindolinone core using sequential cycloadditions. Org Lett. 2009; 11(16):3782-5. PMC: 2736368. DOI: 10.1021/ol901499b. View

11.

Shchegravina E, Maleev A, Ignatov S, Gracheva I, Stein A, Schmalz H . Synthesis and biological evaluation of novel non-racemic indole-containing allocolchicinoids. Eur J Med Chem. 2017; 141:51-60. DOI: 10.1016/j.ejmech.2017.09.055. View

12.

Hagras M, El Deeb M, Elzahabi H, Elkaeed E, Mehany A, Eissa I . Discovery of new quinolines as potent colchicine binding site inhibitors: design, synthesis, docking studies, and anti-proliferative evaluation. J Enzyme Inhib Med Chem. 2021; 36(1):640-658. PMC: 7889231. DOI: 10.1080/14756366.2021.1883598. View

13.

Danieli B, Giardini A, Lesma G, Passarella D, Peretto B, Sacchetti A . Thiocolchicine-podophyllotoxin conjugates: dynamic libraries based on disulfide exchange reaction. J Org Chem. 2006; 71(7):2848-53. DOI: 10.1021/jo052677g. View

14.

Liu X, Hu Y, Chen B, Min L, Peng X, Zhao J . Asymmetric Total Syntheses of Colchicine, β-Lumicolchicine, and Allocolchicinoid N-Acetylcolchinol-O-methyl Ether (NCME). Org Lett. 2017; 19(17):4612-4615. DOI: 10.1021/acs.orglett.7b02224. View

15.

Czerwonka D, Sobczak S, Maj E, Wietrzyk J, Katrusiak A, Huczynski A . Synthesis and Antiproliferative Screening Of Novel Analogs of Regioselectively Demethylated Colchicine and Thiocolchicine. Molecules. 2020; 25(5). PMC: 7179419. DOI: 10.3390/molecules25051180. View

16.

Ghawanmeh A, Chong K, Sarkar S, Abu Bakar M, Othaman R, Khalid R . Colchicine prodrugs and codrugs: Chemistry and bioactivities. Eur J Med Chem. 2017; 144:229-242. DOI: 10.1016/j.ejmech.2017.12.029. View

17.

Morita H, Matsumoto K, Takeya K, Itokawa H . Conformation of tropolone ring in antileukemic tropoloisoquinoline alkaloids. Chem Pharm Bull (Tokyo). 1993; 41(8):1478-80. DOI: 10.1248/cpb.41.1478. View

18.

Lee J, Cha J . Total synthesis of tropoloisoquinolines: imerubrine, isoimerubrine, and grandirubrine. J Am Chem Soc. 2001; 123(14):3243-6. DOI: 10.1021/ja0101072. View

19.

Yan Y, Ma Y, Yang J, Horsman G, Luo D, Ji X . Tropolone Ring Construction in the Biosynthesis of Rubrolone B, a Cationic Tropolone Alkaloid from Endophytic Streptomyces. Org Lett. 2016; 18(6):1254-7. DOI: 10.1021/acs.orglett.6b00074. View

20.

Gasparyan A, Ayvazyan L, Yessirkepov M, Kitas G . Colchicine as an anti-inflammatory and cardioprotective agent. Expert Opin Drug Metab Toxicol. 2015; 11(11):1781-94. DOI: 10.1517/17425255.2015.1076391. View