title: Synthesis and evaluation of 5-(arylthio)-9H-pyrimido[4,5-b]indole-2,4-diamines as receptor tyrosine kinase and thymidylate synthase inhibitors and as antitumor agents.
abstract: In an effort to optimize the structural requirements for combined cytostatic and cytotoxic effects in single agents, a series of 5-(arylthio)-9H-pyrimido[4,5-b]indole-2,4-diamines 3-7 were synthesized and evaluated as inhibitors of receptor tyrosine kinases (RTKs) as well as thymidylate synthase (TS). The synthesis of these compounds involved the nucleophilic displacement of the common intermediate 5-bromo/5-chloro-9H-pyrimido[4,5-b]indole-2,4-diamine with appropriate aryl thiols. A novel four step synthetic scheme to the common intermediate was developed which is more efficient relative to the previously reported six-step sequence. Biological evaluation of these compounds indicated dual activity in RTKs and human TS (hTS). In the VEGFR-2 assay, compound 5 was equipotent to the standard compound semaxanib and was better than standard TS inhibitor pemetrexed, in the hTS assay. Compounds 3, 6 and 7 were nanomolar inhibitors of hTS and were several fold better than pemetrexed.
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States.
authors.forename: Nilesh
authors.initials: N
authors.lastname: Zaware
authors.affiliation: Department of Biochemistry, Tufts University School of Medicine, Boston, MA 02111, United States.
authors.forename: Roy
authors.initials: R
authors.lastname: Kisliuk
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, United States.
authors.forename: Anja
authors.initials: A
authors.lastname: Bastian
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Ihnat
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States. Electronic address: gangjee@duq.edu.
authors.forename: Aleem
authors.initials: A
authors.lastname: Gangjee
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D051379:Mice; D000068437:Pemetrexed / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: C117011:3-(4-dimethylamino-benzylidenyl)-2-indolinone; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D006575:Heterocyclic Compounds, 3-Ring; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D000068437:Pemetrexed; C116890:Semaxinib; D013940:Thymidylate Synthase; D020794:Receptor Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2; D002945:Cisplatin
keywords: Antiangiogenic agents; Combination chemotherapeutic potential in single agents; Multiple receptor tyrosine kinase inhibitors; Pyrimido[4,5-b]indole synthesis; Thymidylate synthase inhibitors