Phytochemicals for the Prevention of Photocarcinogenesis

Ultraviolet (UV) exposure has an array of damaging effects and is the main cause of skin cancer in humans. Nonmelanoma skin cancer (NMSC), including basal cell carcinoma and squamous cell carcinoma, is the most common type of cancer. Incidence of NMSC has increased due to greater UV radiation, increased life expectancy and other changes in lifestyle; the annual cost of skin cancer treatment in the United States has increased concurrently to around eight billion dollars. Because of these trends, novel approaches to skin cancer prevention have become an important area of research to decrease skin cancer morbidity and defray the costs associated with treatment. Chemoprevention aims to prevent or delay the development of skin cancer through the use of phytochemicals. Use of phytochemicals as chemopreventive agents has gained attention due to their low toxicity and anticarcinogenic properties. Phytochemicals also exhibit antioxidant, anti‐inflammatory and antiproliferative effects which support their use as chemopreventive agents, particularly for skin cancer. Preclinical and human studies have shown that phytochemicals decrease UV‐induced skin damage and photocarcinogenesis. In this review article, we discuss the selected phytochemicals that may prevent or delay UV‐induced carcinogenesis and highlight their potential use for skin protection.     

Alternative approaches to potential of mean force calculations: Free energy perturbation versus thermodynamic integration. Case study of some representative nonpolar interactions

We investigated the convergence behavior of potential of mean force (PMF) calculations using free energy perturbation (FEP), thermodynamic integration (TI), and “slow growth” (SG) techniques. The critical comparison of these alternative approaches is illustrated by the study of three different systems: two tagged argon atoms in a periodic box of argon, two methane molecules, and two benzene molecules maintained in a “T-shaped” conformation, both dimers embedded in a periodic box of water. The complete PMF simulations were carried out considering several protocols, in which the number of intermediate “λ” states, together with the amount of sampling per individual state, were varied. In most cases, as much as 1 ns of molecular dynamics (MD) sampling was used to derive each free energy profile. For the different systems examined, we find that FEP and TI unquestionably constitute robust computational methods leading to results of comparable accuracy. We also show that proper convergence of the free energy calculations, and further quantitative interpretation of the PMFs, requires total simulation times much higher than has been hitherto estimated. In some circumstances, the free energy profiles derived from FEP calculations tend to be slightly poorer than those obtained with TI, as a probable consequence of the greater sensitivity of FEP to the window spacing δλ. In the context of TI, and to a lesser extent FEP, simulations, it appears preferable to employ a limited number of “λ” points of the integrand involving extensive sampling, rather than numerous points with fewer samplings. Finally, we note that, at least in the case of nonpolar interactions, PMFs of reasonable quality can be generated using SG, and at a substantially lower cost than with either FEP or TI. © 1996 by John Wiley & Sons, Inc.     

Accuracy of free energies of hydration using CM1 and CM3 atomic charges

Absolute free energies of hydration (DeltaGhyd) have been computed for 25 diverse organic molecules using partial atomic charges derived from AM1 and PM3 wave functions via the CM1 and CM3 procedures of Cramer, Truhlar, and coworkers. Comparisons are made with results using charges fit to the electrostatic potential surface (EPS) from ab initio 6-31G* wave functions and from the OPLS-AA force field. OPLS Lennard-Jones parameters for the organic molecules were used together with the TIP4P water model in Monte Carlo simulations with free energy perturbation theory. Absolute free energies of hydration were computed for OPLS united-atom and all-atom methane by annihilating the solutes in water and in the gas phase, and absolute DeltaGhyd values for all other molecules were computed via transformation to one of these references. Optimal charge scaling factors were determined by minimizing the unsigned average error between experimental and calculated hydration free energies. The PM3-based charge models do not lead to lower average errors than obtained with the EPS charges for the subset of 13 molecules in the original study. However, improvement is obtained by scaling the CM1A partial charges by 1.14 and the CM3A charges by 1.15, which leads to average errors of 1.0 and 1.1 kcal/mol for the full set of 25 molecules. The scaled CM1A charges also yield the best results for the hydration of amides including the E/Z free-energy difference for N-methylacetamide in water.     

Synthesis of N-methyl-N-[(1S)-1-[(3R)-pyrrolidin-3-yl]ethyl]amine

N-Methyl-N-[(1S)-1-[(3R)-pyrrolidin-3-yl]ethyl]amine (1)(1) is a key intermediate in the preparation of premafloxacin (2), which was under development as an antibiotic for use against pathogens of veterinary importance. This paper describes the development of a practical, efficient, and stereoselective process for the preparation of 1 from isobutyl (3S)-3-[methyl[(1S)-1-phenylethyl]amino]butanoate (5c). The key steps in the synthetic sequence are an asymmetric Michael addition, which yields 5c, and a stereoselective alkylation, which yields (3S,4S)-3-allyl-1,4-dimethylazetidin-2-one (17).