Abstract
Pan-Gyn cancers entail 1 in 5 cancer cases worldwide, breast cancer being the most commonly diagnosed and responsible for most cancer deaths in women. The high incidence and mortality of these malignancies, together with the handicaps of taxanes—first-line treatments—turn the development of alternative therapeutics into an urgency. Taxanes exhibit low water solubility that require formulations that involve side effects. These drugs are often associated with dose-limiting toxicities and with the appearance of multi-drug resistance (MDR). Here, we propose targeting tubulin with compounds directed to the colchicine site, as their smaller size offer pharmacokinetic advantages and make them less prone to MDR efflux. We have prepared 52 new Microtubule Destabilizing Sulfonamides (MDS) that mostly avoid MDR-mediated resistance and with improved aqueous solubility. The most potent compounds, N-methyl-N-(3,4,5-trimethoxyphenyl-4-methylaminobenzenesulfonamide 38, N-methyl-N-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide 42, and N-benzyl-N-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide 45 show nanomolar antiproliferative potencies against ovarian, breast, and cervix carcinoma cells, similar or even better than paclitaxel. Compounds behave as tubulin-binding agents, causing an evident disruption of the microtubule network, in vitro Tubulin Polymerization Inhibition (TPI), and mitotic catastrophe followed by apoptosis. Our results suggest that these novel MDS may be promising alternatives to taxane-based chemotherapy in chemoresistant Pan-Gyn cancers.
Highlights
Gynecologic and women breast cancer share relevant similarities at the molecular level that cluster them together (Pan-Gyn) and distinguish them from other tumor types [1,2]
Similar or even better results were obtained when compared with the orally wavelengths of selected compounds was measured after h shaking and subsequent increased aqueous solubility when compared to paclitaxel and to combretastatin A-4 (CA-4)
To determine whether the cytotoxic/antiproliferative effect of the Microtubule Destabilizing Sulfonamides (MDS) was due to apoptosis induction, cells were treated with variable concentrations of the drug for 72 h or days, stained with Annexin V-FITC (AnV) and propidium iodide (PI), and analyzed by flow cytometry
Summary
Gynecologic (i.e., ovarian, uterine, vulva, and vagina) and women breast cancer share relevant similarities at the molecular level that cluster them together (Pan-Gyn) and distinguish them from other tumor types [1,2]. The only approved drugs belong to the vinca alkaloids site binding ligands, which are used against hematological malignancies and solid tumors, including breast cancer. They share with taxanes the problems of toxic side effects, difficult pharmacokinetics, and complex hydrophobic structures that make them substrates of drug efflux pumps [44]. Colchicine-site ligands display antiproliferative effects (characterized by cell cycle arrest at G2 /M phase followed by the induction of apoptosis [45]) and act as vascular disrupting agents, affording additional odds against solid tumors [46] Representatives such as the stilbene combretastatin A-4. Site used as as a starting point for for the the rational design of new MiFigure
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