title: DUPA conjugation of a cytotoxic indenoisoquinoline topoisomerase I inhibitor for selective prostate cancer cell targeting.
abstract: Prostate-specific membrane antigen (PSMA) is overexpressed in most prostate cancer cells while being present at low or undetectable levels in normal cells. This difference provides an opportunity to selectively deliver cytotoxic drugs to prostate cancer cells while sparing normal cells that lack PSMA, thus improving potencies and reducing toxicities. PSMA has high affinity for 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid (DUPA) (Ki = 8 nM). After binding to a DUPA-drug conjugate, PSMA internalizes, unloads the conjugate, and returns to the surface. In the present studies, an indenoisoquinoline topoisomerase I inhibitor was conjugated to DUPA via a peptide linker and a drug-release segment that facilitates intracellular cleavage to liberate the drug cargo. The DUPA-indenoisoquinoline conjugate exhibited an IC50 in the low nanomolar range in 22RV1 cell cultures and induced a complete cessation of tumor growth with no toxicity, as determined by loss of body weight and death of treated mice.
authors.affiliation: ‡Department of Chemistry, College of Science, Purdue University, West Lafayette, Indiana 47907, United States.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Roy
authors.affiliation: †Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United States.
authors.forename: Trung Xuan
authors.initials: TX
authors.lastname: Nguyen
authors.affiliation: ‡Department of Chemistry, College of Science, Purdue University, West Lafayette, Indiana 47907, United States.
authors.forename: Ananda Kumar
authors.initials: AK
authors.lastname: Kanduluru
authors.affiliation: ‡Department of Chemistry, College of Science, Purdue University, West Lafayette, Indiana 47907, United States.
authors.forename: Chelvam
authors.initials: C
authors.lastname: Venkatesh
authors.affiliation: †Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Lv
authors.affiliation: †Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United States.
authors.forename: P V Narasimha
authors.initials: PV
authors.lastname: Reddy
authors.affiliation: ‡Department of Chemistry, College of Science, Purdue University, West Lafayette, Indiana 47907, United States.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Low
authors.affiliation: †Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D005977:Glutarates / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000737:chemistry*; D007610:Kallikreins / Q000378:metabolism*; D008297:Male; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D059004:Topoisomerase I Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: C544380:2-(3-(1,3-dicarboxypropyl)ureido)pentanedioic acid; D000970:Antineoplastic Agents; D005977:Glutarates; D007546:Isoquinolines; D059004:Topoisomerase I Inhibitors; D014508:Urea; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen