Highly active antiretroviral therapy (HAART) decreases plasma viremia below the limits of detection in the majority of HIV-infected individuals, thus serving to slow disease progression. However, HAART targets only actively replicating virus and is unable to eliminate latently infected, resting CD4
+
T cells. Such infected cells are potentially capable of reinitiating virus replication upon cessation of HAART, thus leading to viral rebound. Agents that would eliminate these reservoirs, when used in combination with HAART, could thus provide a strategy for the eradication of HIV. Prostratin is a preclinical candidate that induces HIV expression from latently infected CD4
+
T cells, potentially leading to their elimination through a virus-induced cytopathic effect or host anti-HIV immunity. Here, we report the synthesis of a series of designed prostratin analogs and report in vitro and ex vivo studies of their activity relevant to induction of HIV expression. Members of this series are up to 100-fold more potent than the preclinical lead (prostratin) in binding to cell-free PKC, and in inducing HIV expression in a latently infected cell line and prostratin-like modulation of cell surface receptor expression in primary cells from HIV-negative donors. Significantly, selected members were also tested for HIV induction in resting CD4
+
T cells isolated from infected individuals receiving HAART and were found to exhibit potent induction activity. These more potent agents and by extension related tunable analogs now accessible through the studies described herein should facilitate research and preclinical advancement of this strategy for HIV/AIDS eradication.
The implementation of cyanation chemistry at manufacturing scales using batch equipment can be challenging because of the hazardous nature of the reagents employed and the tight control of reaction parameters, including cryogenic temperatures, that help to afford acceptable selectivity and conversion for the desired reaction. Application of continuous flow chemistry offers a means to mitigate the risk associated with handling large amounts of hazardous reagents and to better control the reaction parameters. A case study describing the cyanation of a glycoside using continuous flow chemistry toward the synthesis of the drug candidate remdesivir is presented.
A threshold collision-induced dissociation (CID) study is performed on dichlorobenzene cation dissociation of both the ortho and para isomers. Ab initio calculations are performed on the system to investigate the details of the potential energy surface with respect to Cl atom loss and to provide the molecular parameters necessary for CID cross section modeling. The effects of kinetic shifts on the CID threshold determinations are investigated using a model that incorporates statistical unimolecular decay theory. The model is tested using unimolecular dissociation rate constants as a function of energy provided by earlier photoelectron–photoion-coincidence (PEPICO) experiments. The different possible sets of parameters involved in the CID model, their effect on the dissociation rates, and their effect on the final CID threshold determination are discussed. A tight transition state is observed to reproduce the experimental dissociation rates better than a phase-space limit loose transition state, a result attributed to a potential energy surface that is much more attractive than a simple ion-induced dipole potential. The dissociation thresholds derived from CID data are in reasonable agreement with the ones derived from fitting the PEPICO rates when similar transition state assumptions are used. A final analysis of the CID data yields 0 K dissociation energies for the Cl atom loss from dichlorobenzene of 3.22±0.17 eV for the ortho isomer and 3.32±0.18 eV for the para isomer. In the present study we support a mechanism that the dissociations of the two isomers proceed through a direct bond cleavage, rather than through isomerization to a common intermediate.
A vinylogous Mukaiyama aldol reaction, conducted using 10 mol % of a BITIP catalyst and B(OMe)3 as an additive, effects an enantioselective four-carbon chain extension to give versatile E-alpha,beta-unsaturated thiol esters.
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