title: Finely Tuned Asymmetric Platinum(IV) Anticancer Complexes: Structure-Activity Relationship and Application as Orally Available Prodrugs.
abstract: 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 PtIVprodrugs 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 PtIVprodrugs may pave the way for a highly predictable, fine-tuned class of orally available PtIVprodrugs for the treatment of colorectal cancer.
authors.affiliation: Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore, 117543, Singapore.
authors.forename: Siew Qi
authors.initials: SQ
authors.lastname: Yap
authors.affiliation: Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore, 117543, Singapore.
authors.forename: Chee Fei
authors.initials: CF
authors.lastname: Chin
authors.affiliation: Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore, 117543, Singapore.
authors.forename: Agnes Hwee
authors.initials: AH
authors.lastname: Hong Thng
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore.
authors.forename: Yi Yun
authors.initials: YY
authors.lastname: Pang
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore.|NUS Graduate School of Integrative Sciences and Engineering, National University of Singapore, 28 Medical Drive, Singapore, 117456, Singapore.
authors.forename: Han Kiat
authors.initials: HK
authors.lastname: Ho
authors.affiliation: Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore, 117543, Singapore.|NUS Graduate School of Integrative Sciences and Engineering, National University of Singapore, 28 Medical Drive, Singapore, 117456, Singapore.
authors.forename: Wee Han
authors.identifier: 0000-0003-2027-356X
authors.initials: WH
authors.lastname: Ang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy; D056831:Coordination Complexes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D004195:Disease Models, Animal; D004355:Drug Stability; D006801:Humans; D051379:Mice; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D010984:Platinum / Q000737:chemistry*; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D012995:Solubility; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014961:X-Ray Diffraction
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D011355:Prodrugs; D010984:Platinum
keywords: anticancer drugs; cisplatin; colorectal cancer; platinum(IV) prodrugs; structure-activity relationships