Kaya Busra, Gholam Azad Mahan, Suleymanoglu Mediha, Harmer Jeffrey R, Wijesinghe Tharushi P, Richardson Vera, Zhao Xiao, Bernhardt Paul V, Dharmasivam Mahendiran, Richardson Des R
Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane 4111, Australia.
Department of Medical Biology, Istanbul Faculty of Medicine, Istanbul University, Fatih, Istanbul 34093, Turkey.
J Med Chem. 2024 Jul 25;67(14):12155-12183. doi: 10.1021/acs.jmedchem.4c00884. Epub 2024 Jul 5.
We implemented isosteric replacement of sulfur to selenium in a novel thiosemicarbazone (PPTP4c4mT) to create a selenosemicarbazone (PPTP4c4mSe) that demonstrates potentiated anticancer efficacy and selectivity. Their design specifically incorporated cyclohexyl and styryl moieties to sterically inhibit the approach of their Fe(III) complexes to the oxy-myoglobin heme plane. Importantly, in contrast to the Fe(III) complexes of the clinically trialed thiosemicarbazones Triapine, COTI-2, and DpC, the Fe(III) complexes of PPTP4c4mT and PPTP4c4mSe did not induce detrimental oxy-myoglobin oxidation. Furthermore, PPTP4c4mSe demonstrated more potent antiproliferative activity than the homologous thiosemicarbazone, PPTP4c4mT, with their selectivity being superior or similar, respectively, to the clinically trialed thiosemicarbazone, COTI-2. An advantageous property of the selenosemicarbazone Zn(II) complexes relative to their thiosemicarbazone analogues was their greater transmetalation to Cu(II) complexes in lysosomes. This latter effect probably promoted their antiproliferative activity. Both ligands down-regulated multiple key receptors that display inter-receptor cooperation that leads to aggressive and resistant breast cancer.
我们在一种新型硫代氨基脲（PPTP4c4mT）中实现了硫到硒的等排取代，以制备一种硒代氨基脲（PPTP4c4mSe），其具有增强的抗癌功效和选择性。它们的设计特别引入了环己基和苯乙烯基部分，以空间位阻方式抑制其Fe(III)配合物接近氧合肌红蛋白血红素平面。重要的是，与临床试用的硫代氨基脲Triapine、COTI-2和DpC的Fe(III)配合物不同，PPTP4c4mT和PPTP4c4mSe的Fe(III)配合物不会诱导有害的氧合肌红蛋白氧化。此外，PPTP4c4mSe比同源硫代氨基脲PPTP4c4mT表现出更强的抗增殖活性，其选择性分别优于或类似于临床试用的硫代氨基脲COTI-2。相对于硫代氨基脲类似物，硒代氨基脲Zn(II)配合物的一个有利特性是它们在溶酶体中向Cu(II)配合物的转金属化能力更强。后一种效应可能促进了它们的抗增殖活性。两种配体均下调了多种关键受体，这些受体表现出受体间的协同作用，导致侵袭性和耐药性乳腺癌。
