Publications

organized by date

 

2018

Tumor-targeting with novel dual-targeted 6-substituted thieno [2, 3-d] pyrimidine antifolates via cellular uptake by folate receptor Alpha, and inhibition of de novo purine …

…, N Tong, C O'Connor, Z Hou, A GangjeeL Matherly… - 2018 - AACR

Epithelial ovarian cancer (EOC) is the deadliest gynecologic cancer, with limited progress in targeted therapy or in combating drug resistance. Reflecting this, there is an urgent need to develop novel inhibitors with minimal toxicity. EOC is associated with increasing expression …



Fluorine-Substituted Pyrrolo[2,3-d]Pyrimidine Analogues with Tumor Targeting via Cellular Uptake by Folate Receptor Alpha and the Proton-Coupled Folate Transporter and …

…, Z Hou, LH Matherly, A Gangjee - Journal of Medicinal …, 2018 - ACS Publications

Novel fluorinated 2-amino-4-oxo-6-substituted pyrrolo [2, 3-d] pyrimidine analogues 7–12 were synthesized and tested for selective cellular uptake by folate receptors (FRs) α and β or the proton-coupled folate transporter (PCFT) and for antitumor efficacy. Compounds 8, 9, 11 …

 

Tumor Targeting with Novel Pyridyl 6-Substituted Pyrrolo[2,3-d]Pyrimidine Antifolates via Cellular Uptake by Folate Receptor Alpha and the Proton-Coupled Folate Transporter and …

…, Z Hou, LH Matherly, A Gangjee - Journal of medicinal …, 2018 - ACS Publications

Tumor-targeted specificities of 6-substituted pyrrolo [2, 3-d] pyrimidine analogues of 1, where the phenyl side-chain is replaced by 3′, 6′(5, 8), 2′, 5′(6, 9), and 2′, 6′(7, 10) pyridyls, were analyzed. Proliferation inhibition of isogenic Chinese hamster ovary (CHO) …



5N-substituted pyrrolo [3, 2-d] pyrimidines: Tumor-targeted agents with first-in-class dual inhibition of serine hydroxymethyl transferase 2 and 5-amino-4 …

K Shah, A Dekhne, Z Hou, L Matherly, A Gangjee - 2018 - AACR

Design, modeling and synthesis of pyrrolo [3, 2-d] pyrimidine analogs were carried out based on the concept of dual mechanisms-of-action for achieving maximal antitumor efficacy. Tumor-targeted delivery via agents that are selectively transported by the folate …



First-in-class, fluorinated folate receptor specific agents that target tumor cells via inhibition of serine hydroxymethyltransferase 2 (SHMT2) and 5-aminoimidazole-4 …

…, K Shah, A GangjeeDekhne, Z Hou, LH Matherly - 2018 - AACR

Tumor-specific folate receptor (FR) targeting over the ubiquitous reduced folate carrier (RFC) allows for specific tumor targeting without the attending dose-limiting toxicity of all clinically used cytotoxic agents. In an attempt to provide selectivity for FRα and/or β, folic …



Structure based drug design and in vitro metabolism study: Discovery of N-(4-methylthiophenyl)-N, 2-dimethyl-cyclopenta [d] pyrimidine as a potent microtubule …

…, E Hamel, SL Mooberry, A Gangjee - Bioorganic & medicinal …, 2018 - Elsevier

We report a series of tubulin targeting agents, some of which demonstrate potent antiproliferative activities. These analogs were designed to optimize the antiproliferative activity of 1 by varying the heteroatom substituent at the 4′-position, the basicity of the 4 …



Folate receptor-targeted cancer chemotherapy with novel 6-substituted thieno [2, 3-d] pyrimidine compounds with nitrogen and fluorine containing aromatic side …

…, A Gangjee, AW Povrik, CO Connor, J Hou, L Matherly - 2018 - AACR

Targeted cancer chemotherapy inhibits the growth of cancer cells by interfering with critical pathways required for tumor progression. Three major transporters are involved in membrane transport of folates into mammalian cells and include the reduced folate carrier …



Dual targeting mitochondrial and cytosolic one-carbon metabolism via the proton-coupled folate transporter with novel 5-substituted pyrrolo [3, 2-d] pyrimidine …

…, Polin, A Gangjee, JD Rabinowitz, LH Matherly - 2018 - AACR

Cellular one-carbon (1C) metabolism generates a host of metabolites especially critical to cancer cells. Classical 1C inhibitors often primarily target a single enzyme, commonly leading to drug resistance and necessitating the development of novel compounds targeting …



The promise and challenges of exploiting the proton-coupled folate transporter for selective therapeutic targeting of cancer

LH Matherly, Z Hou, A Gangjee - Cancer chemotherapy and …, 2018 - Springer

This review considers the “promise” of exploiting the proton-coupled folate transporter (PCFT) for selective therapeutic targeting of cancer. PCFT was discovered in 2006 and was identified as the principal folate transporter involved in the intestinal absorption of dietary …



Development and validation of chemical features-based proton-coupled folate transporter/activity and reduced folate carrier/activity models (pharmacophores)

…, S Raghavan, Z Hou, LH MatherlyA Gangjee - Journal of Molecular …, 2018 - Elsevier

All clinically used antifolates lack transport selectivity for tumors over normal cells resulting in dose-limiting toxicities. There is growing interest in developing novel tumor-targeted cytotoxic antifolates with selective transport into tumors over normal cells via the proton …



Fluorine-Substituted Pyrrolo [23-d] Pyrimidine Analogues with Tumor Targeting via Cellular Uptake by Folate Receptor Alpha and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine …

…, Z Hou, LH MatherlyA Gangjee - Journal of Medicinal …, 2018 - ACS Publications

Novel fluorinated 2-amino-4-oxo-6-substituted pyrrolo [2, 3-d] pyrimidine analogues 7–12 were synthesized and tested for selective cellular uptake by folate receptors (FRs) α and β or the proton-coupled folate transporter (PCFT) and for antitumor efficacy. Compounds 8, 9, 11 …



2017


Selective tumor targeting with 5-substituted pyrrolo[2,3-d]pyrimidines with heteroatom bridge substitution

A Gangjee, R Mohan, M Ravindra, Wallace-Povirk… - 2017 - AACR

Three specialized systems exist for membrane transport of folates and antifolates across biological membranes. The reduced folate carrier (RFC) is ubiquitously expressed in tumors and normal tissues. Folate receptors (FR) α and β, and the proton-coupled folate receptor …

Dual targeting of epithelial ovarian cancer via folate receptor α and the proton-coupled folate transporter with 6-substituted pyrrolo [2, 3-d] pyrimidine antifolates

…, J Kushner, RT Morris, A GangjeeLH Matherly - Molecular cancer …, 2017 - AACR

Folate uptake in epithelial ovarian cancer (EOC) involves the reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT), both facilitative transporters, and folate receptor (FR) α. Whereas in primary EOC specimens, FRα is widely expressed and …

Targeted thieno[2,3-d]pyrimidines with fluorinated phenyl side chains as antitumor agents

N Tong, A Gangjee, AW Povrik, C O'Connor… - 2017 - AACR

The reduced folate carrier (RFC) is ubiquitously expressed in tissues and tumors and is the major tissue transporter for folate cofactors. Folate receptor (FR) α and β, as well as the proton-coupled folate transporter (PCFT), exhibit narrower patterns of tissue expression and …

Correction to Structural and Enzymatic Analysis of Tumor-Targeted Antifolates That Inhibit Glycinamide Ribonucleotide Formyltransferase

SM Deis, Doshi, Z Hou, LH MatherlyA Gangjee… - Biochemistry, 2017 - ACS Publications

Abstract: Pemetrexed and methotrexate are antifolates used for cancer chemotherapy and inflammatory diseases. These agents have toxic side effects resulting, in part, from nonspecific cellular transport by the reduced folate carrier (RFC), a ubiquitously expressed ...