Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and the limited therapeutic options show poor efficacy in patients, associated to severe side effects and development of resistance. Considering that chromene-based scaffolds proved to be attractive candidates for cancer therapy, herein we prepared new chromeno[2,3-d]pyrimidinone derivatives by a simple two step procedure, starting from the reaction of cyanoacetamide and a salicylaldehyde. A cell viability screening in several breast cancer cell lines allowed to identify two promising compounds with IC₅₀ values in the low micromolar range for TNBC cells. These chromenes inhibited cell proliferation, induced cell cycle arrest and triggered cell death through apoptosis. In vivo studies revealed a safe profile in invertebrate and vertebrate animal models and confirmed their capacity to inhibit tumor growth in the CAM model, inducing significant tumor regression after 4 days of treatment. The two compounds identified in this study are promising drug candidates for TNBC treatment and valuable hits for future optimization, using the versatile synthetic platform that was developed.

中文翻译：

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新型色并[2,3-d]嘧啶酮作为三阴性乳腺癌治疗剂的体外和体内评价

三阴性乳腺癌（TNBC）是乳腺癌中最具侵袭性的亚型，有限的治疗选择对患者疗效不佳，并伴有严重的副作用和耐药性的产生。考虑到基于色烯的支架被证明是癌症治疗的有吸引力的候选者，本文中我们从氰基乙酰胺和水杨醛的反应开始，通过简单的两步程序制备了新的色烯基[2,3- d ]嘧啶酮衍生物。对几种乳腺癌细胞系进行的细胞活力筛选能够鉴定出两种有前景的化合物，对于 TNBC 细胞，其 IC ₅₀值在低微摩尔范围内。这些色烯抑制细胞增殖，诱导细胞周期停滞并通过细胞凋亡引发细胞死亡。体内研究揭示了它们在无脊椎动物和脊椎动物模型中的安全性，并证实了它们在 CAM 模型中抑制肿瘤生长的能力，治疗 4 天后诱导肿瘤显着消退。本研究中确定的两种化合物是用于 TNBC 治疗的有前途的候选药物，并且使用所开发的多功能合成平台对未来的优化有价值。