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Novel tricyclic indeno[2,1-d]pyrimidines with dual antiangiogenic and cytotoxic activities as potent antitumor agents.

ABSTRACT: We designed, synthesized and evaluated 13 novel tricyclic indeno[2,1-d]pyrimidines as RTK inhibitors. These analogues were synthesized via a Dieckmann condensation of 1,2-phenylenediacetonitrile followed by cyclocondensation with guanidine carbonate to afford the 2-amino-3,9-dihydro-indeno[2,1-d]pyrimidin-4-one. Sulfonation of the 4-position followed by displacement with appropriately substituted anilines afforded the target compounds. These compounds were potent inhibitors of platelet-derived growth factor receptor ? (PDGFR?) and inhibited angiogenesis in the chicken embryo chorioallantonic membrane (CAM) assay compared to standards. In addition, compound 7 had a two digit nanomolar GI(50) against nine tumor cell lines, a submicromolar GI(50) against 29 of other tumor cell lines in the preclinical NCI 60 tumor cell line panel. Compound 7 also demonstrated significant in vivo inhibition of tumor growth and angiogenesis in a B16-F10 syngeneic mouse melanoma model.

SUBMITTER: Gangjee A

PROVIDER: S-EPMC3397428 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Novel tricyclic indeno[2,1-d]pyrimidines with dual antiangiogenic and cytotoxic activities as potent antitumor agents.

Gangjee Aleem A Zhao Ying Y Ihnat Michael A MA Thorpe Jessica E JE Bailey-Downs Lora C LC Kisliuk Roy L RL

Bioorganic & medicinal chemistry 20120606 14

We designed, synthesized and evaluated 13 novel tricyclic indeno[2,1-d]pyrimidines as RTK inhibitors. These analogues were synthesized via a Dieckmann condensation of 1,2-phenylenediacetonitrile followed by cyclocondensation with guanidine carbonate to afford the 2-amino-3,9-dihydro-indeno[2,1-d]pyrimidin-4-one. Sulfonation of the 4-position followed by displacement with appropriately substituted anilines afforded the target compounds. These compounds were potent inhibitors of platelet-derived g ...[more]

PMID: 22739090

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Project description:Cancer immunotherapy, especially immune checkpoint blockade (ICB), has revolutionized oncology. However, only a limited number of patients benefit from immunotherapy, and some cancers that initially respond to immunotherapy can ultimately relapse and progress. Thus, some studies have investigated combining immunotherapy with other therapies to overcome resistance to monotherapy. Recently, multiple preclinical and clinical studies have shown that tumor vasculature is a determinant of whether immunotherapy will elicit an antitumor response; thus, vascular targeting may be a promising strategy to improve cancer immunotherapy outcomes. A successful antitumor immune response requires an intact "Cancer-Immunity Cycle," including T cell priming and activation, immune cell recruitment, and recognition and killing of cancer cells. Angiogenic inducers, especially vascular endothelial growth factor (VEGF), can interfere with activation, infiltration, and function of T cells, thus breaking the "Cancer-Immunity Cycle." Together with immunostimulation-regulated tumor vessel remodeling, VEGF-mediated immunosuppression provides a solid therapeutic rationale for combining immunotherapy with antiangiogenic agents to treat solid tumors. Following the successes of recent landmark phase III clinical trials, therapies combining immune checkpoint inhibitors (ICIs) with antiangiogenic agents have become first-line treatments for multiple solid tumors, whereas the efficacy of such combinations in other solid tumors remains to be validated in ongoing studies. In this review, we discussed synergies between antiangiogenic agents and cancer immunotherapy based on results from preclinical and translational studies. Then, we discussed recent progress in randomized clinical trials. ICI-containing combinations were the focus of this review because of their recent successes, but combinations containing other immunotherapies were also discussed. Finally, we attempted to define critical challenges in combining ICIs with antiangiogenic agents to promote coordination and stimulate collaboration within the research community.

Dataset Information

Novel tricyclic indeno[2,1-d]pyrimidines with dual antiangiogenic and cytotoxic activities as potent antitumor agents.

Publications

Novel tricyclic indeno[2,1-d]pyrimidines with dual antiangiogenic and cytotoxic activities as potent antitumor agents.

Similar Datasets

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