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  3. Replacing the tropolonic methoxyl group of colchicine with methylamino increases tubulin binding affinity with improved therapeutic index and overcomes paclitaxel cross-resistance

Replacing the tropolonic methoxyl group of colchicine with methylamino increases tubulin binding affinity with improved therapeutic index and overcomes paclitaxel cross-resistance

  • Drug Resist Updat. 2023 May:68:100951. doi: 10.1016/j.drup.2023.100951.
Juanjuan Yang 1,  Dake Song 2,  Bingqian Li 1,  Xiaoxiao Gao 1,  Yuetong Wang 1,  Xiaohu Li 2,  Changshun Bao 2,  Caijiao Wu 2,  Yu Bao 1,  Samuel Waxman 3,  Guoliang Chen 4,  Yongkui Jing 5
Affiliations

Affiliations

  • 1 Liaoning Key Laboratory of Targeting Drugs for Hematological Malignancies, Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 3 The Division of Hematology/Oncology, Department of Medicine, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
  • 4 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: [email protected].
  • 5 Liaoning Key Laboratory of Targeting Drugs for Hematological Malignancies, Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: [email protected].
PMID: 36841134 DOI: 10.1016/j.drup.2023.100951
Abstract

Aims: Microtubule inhibitors are widely used in first line Cancer therapy, though drug resistance often develops and causes treatment failure. Colchicine binds to tubulins and inhibits tumor growth, but is not approved for Cancer therapy due to systemic toxicity. In this study, we aim to improve the therapeutic index of colchicine through structural modification.

Methods: The methoxyl group of the tropolonic ring in colchicine was replaced with amino groups. The cross-resistance of the derivatives with paclitaxel and vincristine was tested. Antitumor effects of target compounds were tested in vivo in A549 and paclitaxel-resistant A549/T xenografts. The interaction of target compounds with tubulins was measured using biological and chemical methods.

Results: Methylamino replacement of the tropolonic methoxyl group of colchicine increases, while demethylation loses, selective tubulin binding affinity, G2/M arrest and antiproliferation activity. Methylaminocolchicine is more potent than paclitaxel and vincristine to inhibit tumor growth in vitro and in vivo without showing cross-resistance to paclitaxel. Methylaminocolchicine binds to tubulins in unique patterns and inhibits P-gp with a stable pharmacokinetic profile.

Conclusion: Methylanimo replacement of the tropolonic methoxyl group of colchicine increases antitumor activity with improved therapeutic index. Methylaminocolchicine represents a new type of mitotic inhibitor with the ability of overcoming paclitaxel and vincristine resistance.

Keywords

Aminocolchicine; Drug resistance; Paclitaxel; Structural modification; Tubulin binding.

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