1,3‐Benzodioxole‐Modified Noscapine Analogues: Synthesis, Antiproliferative Activity, and Tubulin‐Bound Structure

• Published in: ChemMedChem 2021-09, Vol.16 (18), p.2882-2894
• Main Authors: Yong, Cassandra, Devine, Shane M., Abel, Anne‐Catherine, Tomlins, Stefan D., Muthiah, Divya, Gao, Xuexin, Callaghan, Richard, Steinmetz, Michel O., Prota, Andrea E., Capuano, Ben, Scammells, Peter J.
• Format: Article
• Language: English
• Subjects: anti-cancer agents; anti-mitotic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Atomic structure; Breast cancer; Cell Proliferation - drug effects; Crystallography; Cytotoxic agents; Cytotoxicity; Design modifications; Deuteration; Deuterium; Dioxoles - chemical synthesis; Dioxoles - chemistry; Dioxoles - pharmacology; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Efflux; Fluorine; Humans; Lung carcinoma; Melanoma; microtubule targeting agents; Molecular Structure; Non-small cell lung carcinoma; noscapine derivatives; Polymerization - drug effects; Structural analysis; Structure-Activity Relationship; Synthesis; Tubulin; Tubulin - metabolism; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; Tumor Cells, Cultured
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202100363

Since the revelation of noscapine's weak anti‐mitotic activity, extensive research has been conducted over the past two decades, with the goal of discovering noscapine derivatives with improved potency. To date, noscapine has been explored at the 1, 7, 6′, and 9′‐positions, though the 1,3‐benzodioxole motif in the noscapine scaffold that remains unexplored. The present investigation describes the design, synthesis and pharmacological evaluation of noscapine analogues consisting of modifications to the 1,3‐benzodioxole moiety. This includes expansion of the dioxolane ring and inclusion of metabolically robust deuterium and fluorine atoms. Favourable structural modifications were subsequently incorporated into multi‐functionalised noscapine derivatives that also possessed modifications previously shown to promote anti‐proliferative activity in the 1‐, 6′‐ and 9′‐positions. Our research efforts afforded the deuterated noscapine derivative 14 e and the dioxino‐containing analogue 20 as potent cytotoxic agents with EC50 values of 1.50 and 0.73 μM, respectively, against breast cancer (MCF‐7) cells. Compound 20 also exhibited EC50 values of