Finely Tuned Asymmetric Platinum(IV) Anticancer Complexes: Structure–Activity Relationship and Application as Orally Available Prodrugs. (11th January 2017)

• Record Type: Journal Article
• Authors: Yap, Siew Qi; Chin, Chee Fei; Hong Thng, Agnes Hwee; Pang, Yi Yun; Ho, Han Kiat; Ang, Wee Han
• Is Part Of: ChemMedChem. Volume 12:Number 4(2017)
• Page Start: 300
• Page End: 311
• Publication Date: 2017-01-11
• Subjects: anticancer drugs -- cisplatin -- colorectal cancer -- platinum(IV) prodrugs -- structure–activity relationships; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201600577
• Languages: English
• ISSNs: 1860-7179

Abstract

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 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. Abstract : Beauty in asymmetry : A series of asymmetric Pt IV bis‐carboxylates based on the cisplatin template was investigated to establish the correlation between various pharmacological parameters that would be useful for the development of this class of compounds as orally available anticancer prodrugs for colorectal cancer.