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Finely Tuned Asymmetric Platinum(IV) Anticancer Complexes: Structure–Activity Relationship and Application as Orally Available Prodrugs
Author(s) -
Yap Siew Qi,
Chin Chee Fei,
Hong Thng Agnes Hwee,
Pang Yi Yun,
Ho Han Kiat,
Ang Wee Han
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600577
Subject(s) - prodrug , lipophilicity , chemistry , acylation , pharmacophore , combinatorial chemistry , cisplatin , in vivo , solubility , carboxylate , platinum , drug , stereochemistry , pharmacology , organic chemistry , biochemistry , chemotherapy , catalysis , medicine , biology , microbiology and biotechnology , surgery
Platinum(IV) bis‐carboxylates are highly versatile prodrug scaffolds with different axial ligands that can be functionalized while keeping the platinum(II) pharmacophore intact. Using a sequential acylation strategy, we developed a class of Pt IV prodrugs of cisplatin with contrasting lipophilic and hydrophilic ligands. We investigated their stability, reduction rates, lipophilicity, aqueous solubility, and antiproliferative efficacies, and assessed for correlations among the parameters that could be useful in drug design. We showed that compounds with high lipophilicity result in better antiproliferative effects in vitro and in vivo, with one of the three compounds tested showing better efficacy than satraplatin against an animal model of colorectal cancer, owing to its higher solubility and lower reduction rates. Our asymmetric Pt IV prodrugs may pave the way for a highly predictable, fine‐tuned class of orally available Pt IV prodrugs for the treatment of colorectal cancer.