Successful anti-tumor effects with two novel bifunctional chemotherapeutic compounds that combine a LAT1 substrate with cytotoxic moieties in aggressive T-cell lymphomas.

T-cell lymphomas are aggressive neoplasms characterized by poor responses to current chemotherapeutic agents. Expression of the l-type amino acid transporter 1 (LAT 1, SLC7A5) allows for the expansion of healthy T-cell counterparts, and upregulation of LAT1 has been reported in precursor T-cell acute leukemia. Therefore, the expression of LAT1 was evaluated in a cohort of cutaneous and peripheral T-cell lymphomas.

A Novel Blood-Brain Barrier-Permeable Chemotherapeutic Agent for the Treatment of Glioblastoma.

Introduction The standard treatment for glioblastoma (GBM) patients is surgical tumor resection, followed by radiation and chemotherapy with temozolomide (TMZ). Unfortunately, 60% of newly diagnosed GBM patients express high levels of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) and are TMZ-resistant, and all patients eventually become refractory to treatment. The blood-brain barrier (BBB) is an obstacle to the delivery of chemotherapeutic agents to GBM, and BBB-permeable agents that are efficacious in TMZ-resistant and refractory patients are needed.

A Novel Brain-Permeant Chemotherapeutic Agent for the Treatment of Brain Metastasis in Triple-Negative Breast Cancer.

Development of metastases to central nervous system (CNS) is an increasing clinical issue following the diagnosis of advanced breast cancer. The propensity to metastasize to CNS varies by breast cancer subtype. Of the four breast cancer subtypes, triple-negative breast cancers (TNBC) have the highest rates of both parenchymal brain metastasis and leptomeningeal metastasis (LM).

Genetic Engineering in Combination with Semi-Synthesis Leads to a New Route for Gram-Scale Production of the Immunosuppressive Natural Product Brasilicardin A.

Brasilicardin A (1) consists of an unusual anti/syn/anti-perhydrophenanthrene skeleton with a carbohydrate side chain and an amino acid moiety. It exhibits potent immunosuppressive activity, yet its mode of action differs from standard drugs that are currently in use. Further pre-clinical evaluation of this promising, biologically active natural product is hampered by restricted access to the ready material, as its synthesis requires both a low-yielding fermentation process using a pathogenic organism and an elaborate, multi-step total synthesis.

Acamprosate produces its anti-relapse effects via calcium.

Alcoholism is one of the most prevalent neuropsychiatric diseases, having an enormous health and socioeconomic impact. Along with a few other medications, acamprosate (Campral-calcium-bis (N-acetylhomotaurinate)) is clinically used in many countries for relapse prevention. Although there is accumulated evidence suggesting that acamprosate interferes with the glutamate system, the molecular mode of action still remains undefined.

Synthesis and biological evaluation of novel steroidal pyrazoles as substrates for bile acid transporters.

A series of novel steroidal pyrazoles was synthesized as substrates for bile acid transporters to explore their potential as drug carriers. The selected pyrazole fused bile acids were further conjugated with drugs and drug surrogates. Their in vitro transport activities were evaluated in human ileal bile acid transporter (hIBAT) and human liver bile acid transporter (hLBAT) expressing Chinese hamster ovary (CHO)-cells and Xenopus laevis oocytes.

Combinatorial Materials Science and Catalysis.

After forever changing the drug discovery process in the pharmaceutical industry, combinatorial chemistry methodologies are increasingly being applied to the discovery and optimization of more efficient catalysts and materials (see picture). With the advent of new combinatorial synthesis and screening technologies, coupled with integrated data management systems, the application of these technologies to materials science and catalyst research holds tremendous potential and brings high expectations to this new and exciting field.

Design, synthesis and biological evaluation of nonpeptide integrin antagonists.

Recent studies demonstrated that peptide and antibody antagonists of integrin alpha v beta 3 block angiogenesis and tumor growth. In this article, the design, synthesis and biological evaluation of a series of nitroaryl ether-based, nonpeptide mimetics are described. The design of these compounds was based on Merck's arylether/alpha-aminoacid/guanidine framework and incorporates a novel nitroaryl system.