Discovery of florylpicoxamid, a mimic of a macrocyclic natural product.

Natural products have routinely been used both as sources of and inspiration for new crop protection active ingredients. The natural product UK-2A has potent anti-fungal activity but lacks key attributes for field translation. Post-fermentation conversion of UK-2A to fenpicoxamid resulted in an active ingredient with a new target site of action for cereal and banana pathogens.

Characterization of designed, synthetically accessible bryostatin analog HIV latency reversing agents.

HIV latency in resting CD4+ T cell represents a key barrier preventing cure of the infection with antiretroviral drugs alone. Latency reversing agents (LRAs) can activate HIV expression in latently infected cells, potentially leading to their elimination through virus-mediated cytopathic effects, host immune responses, and/or therapeutic strategies targeting cells actively expressing virus. We have recently described several structurally simplified analogs of the PKC modulator LRA bryostatin (termed bryologs) designed to improve synthetic accessibility, tolerability in vivo, and efficacy in inducing HIV latency reversal.

REDOR NMR Reveals Multiple Conformers for a Protein Kinase C Ligand in a Membrane Environment.

Bryostatin 1 (henceforth bryostatin) is in clinical trials for the treatment of Alzheimer's disease and for HIV/AIDS eradication. It is also a preclinical lead for cancer immunotherapy and other therapeutic indications. Yet nothing is known about the conformation of bryostatin bound to its protein kinase C (PKC) target in a membrane microenvironment.

In vivo activation of latent HIV with a synthetic bryostatin analog effects both latent cell "kick" and "kill" in strategy for virus eradication.

The ability of HIV to establish a long-lived latent infection within resting CD4+ T cells leads to persistence and episodic resupply of the virus in patients treated with antiretroviral therapy (ART), thereby preventing eradication of the disease. Protein kinase C (PKC) modulators such as bryostatin 1 can activate these latently infected cells, potentially leading to their elimination by virus-mediated cytopathic effects, the host's immune response and/or therapeutic strategies targeting cells actively expressing virus. While research in this area has focused heavily on naturally-occurring PKC modulators, their study has been hampered by their limited and variable availability, and equally significantly by sub-optimal activity and in vivo tolerability.

Simplified Bryostatin Analogues Protect Cells from Chikungunya Virus-Induced Cell Death.

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus showing a recent resurgence and rapid spread worldwide. While vaccines are under development, there are currently no therapies to treat this disease, except for over-the-counter (OTC) analgesics, which alleviate the devastating arthritic and arthralgic symptoms. To identify novel inhibitors of the virus, analogues of the natural product bryostatin 1, a clinical lead for the treatment of cancer, Alzheimer's disease, and HIV eradication, were investigated for in vitro antiviral activity and were found to be among the most potent inhibitors of CHIKV replication reported to date.

Toward a biorelevant structure of protein kinase C bound modulators: design, synthesis, and evaluation of labeled bryostatin analogues for analysis with rotational echo double resonance NMR spectroscopy.

Protein kinase C (PKC) modulators are currently of great importance in preclinical and clinical studies directed at cancer, immunotherapy, HIV eradication, and Alzheimer's disease. However, the bound conformation of PKC modulators in a membrane environment is not known. Rotational echo double resonance (REDOR) NMR spectroscopy could uniquely address this challenge.

Designed, synthetically accessible bryostatin analogues potently induce activation of latent HIV reservoirs in vitro.

Bryostatin is a unique lead in the development of potentially transformative therapies for cancer, Alzheimer's disease and the eradication of HIV/AIDS. However, the clinical use of bryostatin has been hampered by its limited supply, difficulties in accessing clinically relevant derivatives, and side effects. Here, we address these problems through the step-economical syntheses of seven members of a new family of designed bryostatin analogues using a highly convergent Prins-macrocyclization strategy.

Translating Nature's Library: The Bryostatins and Function-Oriented Synthesis.

We review in part our computational, design, synthesis, and biological studies on a remarkable class of compounds and their designed analogs that have led to preclinical candidates for the treatment of cancer, a first-in-class approach to Alzheimer's disease, and a promising strategy to eradicate HIV/AIDS. Because these leads target, in part, protein kinase C (PKC) isozymes, they have therapeutic potential even beyond this striking set of therapeutic indications. This program has given rise to new synthetic methodology and represents an increasingly important direction of synthesis focused on achieving function through synthesis-informed design (function-oriented synthesis).

Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity.

Modern methods for the identification of therapeutic leads include chemical or virtual screening of compound libraries. Nature's library represents a vast and diverse source of leads, often exhibiting exquisite biological activities. However, the advancement of natural product leads into the clinic is often impeded by their scarcity, complexity, and nonoptimal properties or efficacy as well as the challenges associated with their synthesis or modification.

In vitro biostability evaluation of polyurethane composites in acidic, basic, oxidative, and neutral solutions.

New and improved properties can often be achieved by compounding two or more different but compatible materials. But, can failure possibility also be increased by such a compounding strategy? In this article, we compared the in vitro biostability of composites with that of the pure polymer. We tested three model composites in oxidative, acidic, basic, and neutral solutions.

Kinetics and time-temperature equivalence of polymer degradation.

We studied the hydrolysis kinetics of amorphous polylactide. It was found the hydrolysis rate had a slow-to-fast transition at a certain molecular weight (Mn). This transition was not correlated with the mass loss and water uptake of samples, nor the pH values of testing media.