Fluorinated cyclic thiosulfonates as anti-cancer agents against EGFR+ and HER2+ breast cancers: Synthesis & formulation

Zaafir M. Dulloo, Elham Yaaghubi, Amanda F. Ghilardi, Ion Ghiviriga, Brian K. Law, and Ronald K. Castellano*

University of Florida

Cancer continues to be one of the leading causes of death worldwide, and breast cancer (BC) is an important contributor to cancer mortality. BC is a heterogeneous disease divided into 4 main subtypes based on the level of expression of estrogen and progesterone receptors, and human epidermal growth factor receptors (EGFR, HER2, and HER3). Functional redundancy among the EGFR family members renders target-specific BC treatments ineffective and leads to resistance and cancer recurrence.

Present shortcomings in the treatment of BC motivated our research efforts from which a new class of anti-BC compounds called Disulfide-bond Disruptive Agents (DDAs) has emerged. DDAs possess the unique ability to downregulate all EGFR family members in parallel and to selectively kill EGFR-overexpressing (EGFR+) and HER2+ BC cells with no evidence of toxicity in vivo. From previously established structure-activity relationships in our group, we inferred that lipophilicity closely modulates DDA potency likely by improving cell membrane permeability. As such, the focus of this work is: (1) To synthesize a small library of fourth-generation DDAs with CF₃ groups, and (2) to study the effects of formulation with beta-cyclodextrin (BCD), both natural and synthetically derived, on DDA aqueous solubility, metabolic stability, and resulting cytotoxicity.

Fluorinated DDAs are attractive targets because of fluorine’s well-established ability to increase lipophilicity and metabolic stability. CF₃ groups were appended to the DDA precursor scaffold through epoxide ring opening to form a diol and subsequent conversion of the hydroxyl groups to CF₃. The pharmacophore will be obtained through reduction of the esters followed by mesylation, thiolation, and oxidation to afford the final compound, dOCF₃tcyDTDO. The library of CF₃-DDAs will also be furnished with candidates bearing moieties that showed promise in previous generations of compounds such as F or OCH₃. Additionally, inclusion complexes (ICs) of tcyDTDO, a second-generation DDA, with BCD and its derivative 2-hydroxypropyl-β-CD (HPB) were prepared and characterized by FT-IR, ¹H-NMR, and phase-solubility studies. The combined results pointed to the successful encapsulation of tcyDTDO in both cases with a 1:1 host-guest stoichiometry, and stability constants (K) of 4790 (BCD) and 76.5 (HPB). Increased water-solubility of up to 85-fold was observed with HPB. Thermodynamic studies are currently underway to better understand the host-guest behavior.

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