Water-soluble prodrugs of paclitaxel containing self-immolative disulfide linkers. Issue 1 (1st January 2015)

• Record Type: Journal Article
• Authors: Gund, Machhindra; Khanna, Amit; Dubash, Nauzer; Damre, Anagha; Singh, Kishore S.; Satyam, Apparao
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 1(2015)
• Page Start: 122
• Page End: 127
• Publication Date: 2015-01-01
• Subjects: Water-soluble prodrugs of paclitaxel -- Self-immolative linkers -- Disulfide linkers -- Sulfhydryl-assisted cleavage of disulfide linkers; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2014.10.088
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: We report here a new series of prodrugs of paclitaxel containing self-immolative disulfide linkers with improved water-solubility, in vitro anticancer activity and oral bioavailability when compared to those of paclitaxel. The disulfide bond in these prodrugs can undergo sulfhydryl-assisted cleavage to release paclitaxel in vivo by a plausible mechanism as shown in the scheme. Abstract: A new series of disulfide-containing prodrugs of paclitaxel were designed, synthesized and evaluated against 6 cancer cell lines. Some of these prodrugs exhibited nearly equal or slightly better anticancer activity when compared to that of paclitaxel. These prodrugs contain water-soluble groups such as amino, carboxyl, hydroxyl, amino acids, etc., and exhibited 6–140 fold increase in aqueous solubility when compared to paclitaxel. One of these prodrugs exhibited improved water solubility, better in vitro anticancer activity and significantly superior oral bioavailability in mice when compared to those of paclitaxel. Thus, we have identified a very promising lead compound for further optimization and evaluation as a potentially bioavailable water-soluble prodrug of paclitaxel.