Though anitumor antimitotic agents are some of the most successful anticancer agents, such as taxanes, these agents are plagued by numerous drawbacks that are the cause of chemotherapy failure. In Preliminary Studies we have discovered a unique set of antitumor antimitotics that: 1) possess a broad spectrum of potent antitumor activity (60 tumor cell lines at nanomolar GI50);2) circumvent tumor resistance due to overexpression of P-glycoprotein (MDR) and/or ?III-tubulin, two of the major clinically relevant tumor resistance mechanisms that hinder antitubule activity of the taxanes and other antimitotics;3) are highly water soluble, thus overcome the lack of water solubility that continue to plague a large number of antimitotics including the newly approved ixabepilone;4) are selective for tumor cells over normal cells;5) bind to or near the colchicine-site in tubulin;and 6) are highly efficacious in tumor xenograft without toxicity. The analogs proposed for optimization of the lead compounds are easily synthesized as water soluble salts. The analogs will be evaluated as inhibitors of tumor cells and tubulin assembly in vitro and active compounds will be prioritized for further studies in three xenograft models and in Taxol resistant tumors in vivo murine tumor models. These results will allow the development of pharmacophores that will provide other molecules to be synthesized.
The Specific Aims of this project are: 1) to synthesize and optimize the activities of lead compounds;2) to evaluate the activities of the synthesized analogs as inhibitors of tumor cells in culture and of tubulin assembly and mechanistic studies;3) to evaluate prioritized, selected analogs in vivo in sensitive and resistant murine tumor models. The broad long term goals of this project are to optimize these novel agents to allow the selection of a candidate or candidates for Phase I clinical trials as antitumor agent(s) to be used alone or in combination with other antitumor agents (including other antimitotics) as well as radiation for the treatment of a broad spectrum of cancers and to fill an unmet need for patients with antitubulin resistant diseases.
Tumor resistance, lack of selectivity and poor water solubility are three of the most important factors responsible for cancer treatment failures. We have discovered new agents with potent antitumor activity, water soluble agents that overcome tumor resistance to some of the most widely used anticancer drugs. This study intends to develop an understanding of the important parts of these drugs to its anticancer activity and its ability to overcome resistance and to develop new drugs with better properties that can be advanced to human trials against a variety of tumors including resistant tumors.
|Pavana, Roheeth Kumar; Shah, Khushbu; Gentile, Taylor et al. (2018) Sterically induced conformational restriction: Discovery and preclinical evaluation of novel pyrrolo[3,2-d]pyrimidines as microtubule targeting agents. Bioorg Med Chem 26:5470-5478|
|Xiang, Weiguo; Choudhary, Shruti; Hamel, Ernest et al. (2018) Structure based drug design and in vitro metabolism study: Discovery of N-(4-methylthiophenyl)-N,2-dimethyl-cyclopenta[d]pyrimidine as a potent microtubule targeting agent. Bioorg Med Chem 26:2437-2451|
|Pavana, Roheeth Kumar; Choudhary, Shruti; Bastian, Anja et al. (2017) Discovery and preclinical evaluation of 7-benzyl-N-(substituted)-pyrrolo[3,2-d]pyrimidin-4-amines as single agents with microtubule targeting effects along with triple-acting angiokinase inhibition as antitumor agents. Bioorg Med Chem 25:545-556|
|Devambatla, Ravi Kumar Vyas; Li, Wei; Zaware, Nilesh et al. (2017) Design, synthesis, and structure-activity relationships of pyrimido[4,5-b]indole-4-amines as microtubule depolymerizing agents that are effective against multidrug resistant cells. Bioorg Med Chem Lett 27:3423-3430|
|Rohena, Cristina C; Risinger, April L; Devambatla, Ravi Kumar Vyas et al. (2016) Janus Compounds, 5-Chloro-N?-methyl-N?-aryl-9H-pyrimido[4,5-b]indole-2,4-diamines, Cause Both Microtubule Depolymerizing and Stabilizing Effects. Molecules 21:|
|Devambatla, Ravi Kumar Vyas; Namjoshi, Ojas A; Choudhary, Shruti et al. (2016) Design, Synthesis, and Preclinical Evaluation of 4-Substituted-5-methyl-furo[2,3-d]pyrimidines as Microtubule Targeting Agents That Are Effective against Multidrug Resistant Cancer Cells. J Med Chem 59:5752-65|
|Zhang, Xin; Raghavan, Sudhir; Ihnat, Michael et al. (2015) The design, synthesis and biological evaluation of conformationally restricted 4-substituted-2,6-dimethylfuro[2,3-d]pyrimidines as multi-targeted receptor tyrosine kinase and microtubule inhibitors as potential antitumor agents. Bioorg Med Chem 23:2408-23|
|Zhang, Xin; Raghavan, Sudhir; Ihnat, Michael et al. (2014) The design and discovery of water soluble 4-substituted-2,6-dimethylfuro[2,3-d]pyrimidines as multitargeted receptor tyrosine kinase inhibitors and microtubule targeting antitumor agents. Bioorg Med Chem 22:3753-72|
|Gangjee, Aleem; Zaware, Nilesh; Devambatla, Ravi Kumar Vyas et al. (2013) Synthesis of N(4)-(substituted phenyl)-N(4)-alkyl/desalkyl-9H-pyrimido[4,5-b]indole-2,4-diamines and identification of new microtubule disrupting compounds that are effective against multidrug resistant cells. Bioorg Med Chem 21:891-902|
|Gangjee, Aleem; Zhao, Ying; Raghavan, Sudhir et al. (2013) Structure-activity relationship and in vitro and in vivo evaluation of the potent cytotoxic anti-microtubule agent N-(4-methoxyphenyl)-N,2,6-trimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-aminium chloride and its analogues as antitumor agents. J Med Chem 56:6829-44|
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