Novel 5-substituted, 2,4-diaminofuro[2,3-d]pyrimidines as multireceptor tyrosine kinase and dihydrofolate reductase inhibitors with antiangiogenic and antitumor activity.
Recent evidence suggests that combination therapy of cancer with receptor tyrosine kinase (RTK) inhibitors, which are usually cytostatic, with conventional chemotherapeutic agents, which are usually cytotoxic, provide an improved treatment option. We have designed, synthesized, and evaluated a series of novel 2,4-diamino-5-substituted furo[2,3-d]pyrimidines with RTK and dihydrofolate reductase (DHFR) inhibitory activity in single molecules, as potential cytostatic and cytotoxic agents with antitumor activity. These compounds were synthesized from 2,4-diamino-5-chloromethyl furo[2,3-d]pyrimidine and aryl methyl ketones using the Wittig reaction to afford the C-8-C-9 unsaturated analogs followed by catalytic reduction to the corresponding saturated compounds. The saturated and unsaturated C-8-C-9 bridged compounds were evaluated as inhibitors of vascular endothelial growth factor receptor (VEGFR-2, Flk, KDR), epidermal growth factor receptor, and platelet-derived growth factor receptor-beta (PDGFR-beta). Selected analogs were also evaluated as antiangiogenic agents in the chicken embryo chorioallantoic membrane (CAM) assay. The compounds were also evaluated as inhibitors of human (h) DHFR and Toxoplasma gondii (tg) DHFR. In each evaluation, a known standard compound was used as a comparison. Of the compounds evaluated, compound 32 was as potent as the standard compounds against VEGFR-2 and PDGFR-beta, showing dual inhibitory activity against RTK. This analog was also highly effective in the CAM assay. A second analog 18 also demonstrated dual VEGFR-2 and PDGFR-beta inhibitory activity as well as potent antiangiogenic activity in the CAM assay. Four additional analogs were also effective against PDGFR-beta and in the CAM assay. An unsaturated C-8-C-9 moiety was necessary for RTK inhibitory activity. Compound 32 also showed inhibitory activity against hDHFR and tgDHFR, illustrating the multitarget inhibitory potential of these analogs. The biological activity of these analogs also suggests the necessity of an unsaturated C-8-C-9 bridge for dual RTK and DHFR inhibitory activity. Compounds 18 and 32 were also evaluated in a B16 melanoma mouse model and were found to be more active as antitumor agents than methotrexate. In addition, both 18 and 32 were also active in decreasing lung metastases in a mouse model of B16 melanomas.
Gangjee
Aleem
A
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA. ganjee@duq.edu
Zeng
Yibin
Y
Ihnat
Michael
M
Warnke
Linda A
LA
Green
Dixy W
DW
Kisliuk
Roy L
RL
Lin
Fu-Tyan
FT
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004354:Drug Screening Assays, Antitumor; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000187:drug effects*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D011743:Pyrimidines; D013762:Tetrahydrofolate Dehydrogenase; D020794:Receptor Protein-Tyrosine Kinases; D008727:Methotrexate