Design, synthesis and SAR study of 3rd-generation taxoids bearing 3-CH3, 3-CF3O and 3-CHF2O groups at the C2-benzoate position

• Published in: Bioorganic chemistry Vol. 95; p. 103523
• Main Authors: Wang, Changwei, Wang, Xin, Sun, Yi, Taouil, Adam K., Yan, Su, Botchkina, Galina I., Ojima, Iwao
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.01.2020; Elsevier
• Subjects: 3rd-generation taxoid; Biochemistry & Molecular Biology; Cancer stem cells; Chemistry; Chemistry, Organic; Difluoromethoxy; Fluorine-containing; Life Sciences & Biomedicine; Multidrug resistance; Physical Sciences; SAR study; Science & Technology; Taxane; Trifluoromethoxy; Fluorine-containing; Trifluoromethoxy; SAR; Multidrug resistance; Taxane; SAR study; ADCs; HCT116CSC; MMPA; 3rd-generation taxoid; Difluoromethoxy; RI; MDR; PPT2; Cancer stem cells; DPBS; MOA; CSCs; STRATEGIC INCORPORATION; PHARMACEUTICALS; ANTICANCER AGENTS; ORTHOGONAL MULTIPOLAR INTERACTIONS; MEDICINAL CHEMISTRY; THROMBIN INHIBITORS; FLUORINE SCAN; BIOLOGICAL EVALUATION; SECO-TAXOIDS; MOLECULAR-FORCE FIELD
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.103523

[Display omitted] •Strategic incorporation of OCF3 and OCHF2 groups to 3rd-generation taxoids.•Novel 3rd-generation taxoids possess excellent potency against MDR cancer cells.•SAR analysis based on cytotoxicity of novel taxoids in various cancer cell lines.•Novel taxoids exhibit good potency against cancer stem cells.•Novel taxoids bearing 3-OCHF2 at the C2-benzoate exhibit the best potency. It has been shown that inclusion of CF3O and CHF2O groups to drug candidates often improve their pharmacological properties, especially metabolic stability, membrane permeability and PK profile. Moreover, the unique non-spherical structure of the OCHF2 group can provide interesting and beneficial characteristics. Accordingly, new 3rd-generation taxoids, bearing 3-OCF3 or 3-OCF2H (and 3-CH3 for comparison) at the C2 benzoate moiety, were synthesized and their potencies against drug-sensitive and drug-resistant cancer cell lines examined. In this study, our previous SAR studies on 3rd-generation taxoids were expanded to disclose that CH3, CF3O and CHF2O groups are well tolerated at this position and enhance potency, especially against MDR-cancer cell lines so that these taxoids can virtually overcome MDR. These new taxoids exhibit up to 7 times higher cytotoxicity (IC50) than paclitaxel against drug-sensitive cancer cell lines (MCF7 and LCC6-WT) and 2–3 orders of magnitude higher potency than paclitaxel against drug-resistant ovarian, breast and colon cancer cell lines with MDR-phenotype (NCI/ADR, LCC6-MDR and LDL-1), as well as pancreatic cancer cell line, CFPAC-1. Since it has been shown that a bulky group at this position reduces potency, it is noteworthy that rather bulky CF3O and CHF2O groups are well tolerated. Molecular modeling analysis indicated the favorable van der Waals interactions of CF3O and CHF2O groups in the binding site. It is also worthy of note that new taxoids, bearing a CHF2O group at the C2 benzoate position (1-06 series), exhibited the highest potencies against MDR-cancer cell lines and cancer stem cell (CSC)-enriched cancer cell lines. These new 3rd-generation taxoids are promising candidates for highly potent chemotherapeutic agents, as well as payloads for tumor-targeting drug conjugates such as antibody-drug conjugates (ADCs).