Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 63, Issue 22, Pages 13899-13912Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c01435
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Funding
- National Natural Science Foundation of China [81822041, 21977116, 81673305, 81773573]
- National Science & Technology Major Project Key New Drug Creation and Manufacturing Program [2018ZX09711002-006-013]
- open project of State Key Laboratory of Natural Medicines [SKLNMZZCX201824, SKLNMZZ202029]
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia Fund [SKL-HIDCA-2018-1]
- Funding of Double First-Rate Discipline Construction [CPU2018GY06, CPU2018GY18]
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Bioorthogonal decaging reactions for controllable drug activation within complex biological systems are highly desirable yet extremely challenging. Herein, we find a new class of Pt(II)-triggered bioorthogonal cleavage reactions in which Pt(II) but not Pt(IV) complexes effectively trigger the cleavage of O/N-propargyl in a variety of ranges of caged molecules under biocompatible conditions. Based on these findings, we propose a general strategy for integrated bioorthogonal prodrugs and accordingly design a prodrug 16, in which a Pt(IV) moiety is covalently connected with an O-2-propargyl diazeniumdiolate moiety. It is found that 16 can be specifically reduced by cytoplasmic reductants in human ovarian cancer cells to liberate cisplatin, which subsequently stimulates the cleavage of O-2-propargyl to release large amounts of NO in situ, thus generating synergistic and potent tumor suppression activity in vivo. Therefore, Pt(II)-triggered depropargylation and the integration concept might provide a general strategy for broad applicability of bioorthogonal cleavage chemistry in vivo.
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