Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Facultad de Farmacia, Universidad de Salamanca, 37007 Salamanca, Spain.
Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, 37007 Salamanca, Spain.
Int J Mol Sci. 2021 Feb 14;22(4):1907. doi: 10.3390/ijms22041907.
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, -methyl--(3,4,5-trimethoxyphenyl-4-methylaminobenzenesulfonamide , -methyl--(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide , and -benzyl--(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide 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.
全球范围内，每五例癌症病例中就有 1 例是妇科癌症，乳腺癌是最常见的诊断类型，也是女性癌症死亡的主要原因。这些恶性肿瘤的发病率和死亡率都很高，加上紫杉醇类药物作为一线治疗的局限性，使得开发替代疗法成为当务之急。紫杉醇类药物水溶性低，需要使用会产生副作用的制剂。这些药物常与剂量限制性毒性和多药耐药性（MDR）相关联。在这里，我们建议使用针对秋水仙碱结合位点的化合物来靶向微管蛋白，因为它们的体积较小，具有药代动力学优势，并且不太容易产生 MDR 外排。我们已经制备了 52 种新的微管不稳定磺酰胺（MDS），它们大多避免了 MDR 介导的耐药性，并且具有改善的水溶解度。最有效的化合物为 -甲基--(3,4,5-三甲氧基苯基-4-甲基氨基苯磺酰胺 、-甲基--(3,4,5-三甲氧基苯基-4-甲氧基-3-氨基苯磺酰胺 和 -苄基--(3,4,5-三甲氧基苯基-4-甲氧基-3-氨基苯磺酰胺 ，对卵巢癌、乳腺癌和宫颈癌细胞具有纳摩尔级的抗增殖活性，与紫杉醇相当甚至更好。这些化合物表现为微管结合剂，在体外导致微管网络明显破坏、微管蛋白聚合抑制（TPI）以及有丝分裂灾难后凋亡。我们的研究结果表明，这些新型 MDS 可能是治疗耐药性妇科癌症中基于紫杉醇的化疗的有前途的替代方案。
