Kim, Straub, and Keyes introduced the statistical temperature molecular dynamics (STMD) algorithm to overcome broken ergodicity by sampling a non­-Boltzmann flat energy histogram as noted in Kim, Straub, and Keyes, Phys. Rev. Lett. 97: 050601 (2007). Canonical averages are calculated via reweighting to the desired temperature. While STMD is promising, its application has been almost entirely to simple or model systems. In this dissertation the implementation of STMD into the biosimulation package CHARMM is used to simulate the methionine enkephalin pentamer peptide with a methione terminal cap in a droplet of CHARMM TIP3P water molecules. Chain thermodynamics is analyzed from the novel perspective of the statistical temperature as a function of potential energy, $TS(U), automatically generated by STMD. Both the minimum in the slope of $TS(U), and the peak in the heat capacity as a function of temperature, calculated via reweighting, indicate a collapse transition at Tθ ≈ 253K. Distributions of dihedral angles are obtained as a function of temperature. Rotamer regions found in the literature are reproduced, along with unique regions not found previously, including with advanced algorithms, indicating the power of STMD enhanced sampling.

<p> The nitrogen and hydrogen-deuterium isotope effects have been measured for the base-promoted elimination reactions of cis-and trans-2-phenylcyclopentyltrimethylammonium ions and cis-and trans-2-phenylcyclohexyltrimethylammonium ions. The observations have been interpr eted as indicative of a concerted E2 mechanism for both trans and cis elimination processes. In the cis eliminations, however, proton transfer to base is far advanced at the transition state resulting in a much higher degree of carbanionic character ass ociated with the transition state than for the trans eliminations. </p> <p> The kinetic isotope effect results for these cyclic systems establish that the two bond-rupture processes complement each other; the greater the extent of proton transfer to base at the transition state, the smaller is the extent of C-N bond weakening. These observations are interpreted in terms of the coupling of the motion which extends the lengths of the H-C and C-N bonds at the transition state and the approach to coplanarity of the bonds involved in the elimination process. </p> / Thesis / Doctor of Philosophy (PhD)

Based on the success of diacyl-tert-butylhydrazines RH-5849 and RH-1266 in controlling agricultural crop pests, we endeavored to synthesize our own diacylbenzyl- and arylhydrazine derivatives for use against the malaria vector Anopheles gambiae. In the process of producing a library of compounds for assay against An. gambiae, it became clear that employing regioselective acylation techniques (in molecules that feature two nucleophilic, acyclic nitrogen atoms α to one another) would be imperative. Synthesis of the library derivatives proceeded rapidly and after topical assay, we found three compounds that were more toxic than the RH-series leads. One of the three displayed an LD50 value of half that of RH-1266, though patch clamp assay concluded that toxicity was not necessarily linked to inhibition of mosquito K+ channel Kv2.1. The acylation of monoarylhydrazines appears simple, but its regioselectivity is poorly understood when assumed as a function of basicity correlating to nucleophilic strength. We determined the ratio of the rate constants for distal to proximal N-acylation using 19F NMR spectroscopic analysis of reactions of 4-fluorophenylhydrazine with limiting (0.2 equiv) acylating agent in the presence of various bases. Acid anhydrides gave consistent preference for distal acylation. The selectivity of acylation by acyl chlorides when using pyridine gives strong distal preference, whereas use of triethylamine or aqueous base in conjunction with aroyl chlorides showed a moderate preference for proximal acylation. This observation yielded a convenient one-step method to synthesize proximal aroylarylhydrazines in yields comparable or superior to that provided by the standard three-step literature approach. Combined with NMR evidence of the distal nitrogen as the unambigiously stronger base of the two nitrogens, we propose a single electron transfer mechanism that predicts the regiochemistry of arylhydrazines toward acylating agents better than the nucleophilicity model based on pKa values. While synthesizing the acylhydrazine library for assay against An. gambiae, NMR spectroscopy revealed rotational isomerisms of two types: chiral helicity (M)/(P) and acyl (E)/(Z)-isomerism due to hindered rotation. Variable temperature NMR allowed the measurement of N-N bond rotational barriers, as well as estimate the barrier of (E)/(Z) interconversion. We obtained the X-ray crystal structures of four diacylhydrazines to test this hypothesis and revealed both the twist conformation around the N-N bond axis and (E)/(Z)-isomerism around the proximal acyl group. Computation (which agreed with the crystal structures) allowed us to estimate which (E)/(Z)-isomers were most likely being observed in solution at room temperature by NMR spectroscopy. In addition, we were able to calculate transition structures corresponding to N-N bond rotational barriers of (E,Z)- and (Z,Z)-isomers of model molecules and rationalize the difference in coalescence temperatures between (E,Z)- and (Z,Z)-isomers. / Ph. D.

Les résistances aux traitements actuels contre le cancer imposent de trouver de nouvelles cibles thérapeutiques. Une de ces cibles est le réseau vasculaire assurant un apport suffisant en nutriments et en oxygène à la tumeur, et permettant l’apparition de métastases. Détruire la vascularisation de la tumeur par l’utilisation d’agents antivasculaires (VDA)revient à l’asphyxier et à l’affamer, inhibant ainsi la prolifération des cellules tumorales et empêchant le processus métastatique. L’objectif de ce travail de thèse a été d’étudier des analogues contraints de l’isocombrétastatine A-4 (isoCA-4), une molécule phare du laboratoire, ayant un excellent pouvoir d’inhibition de la polymérisation de la tubuline et présentant une activité antivasculaire. Ces structures dont la double liaison est incluse dans différents types de cycles C,ont été étudiées également afin d’évaluer l’influence de l’angle dièdre formé par les noyaux A et B sur les activités biologiques des divers types de structures. Préalablement sélectionnés par modélisation moléculaire, ces analogues contraints sont de type 1-arylnaphtalène, 5-arylbenzoxépine ou 4-arylchromène et ont été préparés par des voies d’ accès originales développées dans le cadre de cette thèse. Parmi les composés synthétisés, l’analogue de type benzoxépine 3-53est aussi cytotoxique que l’isoCA-4 et possède un pouvoir d’inhibition de la polymérisation de la tubuline équivalent. Une évaluation plus poussée de son profil biologique, ainsi que celle des meilleurs représentants de chaque série chimique est actuellement en cours. / Most tumor cells rely on an efficient vascular supply for their survival, making the tumor vasculature an attractive target for anti-cancer therapy. This thesis aimed at the design and synthesis of constrained analogues of isocombretastatin A-4(isoCA-4), an antivascular agent developed in the laboratory, which exerts excellent cytotoxicities against a large panel ofcancer cell lines, and strongly inhibits tubulin polymerization. Conformationally restricted analogues of isoCA-4,featuring 1-arylnaphthalene, 5-arylbenzoxepine or 4-arylchromene skeletons were designed by computational studies andprepared by novel synthetic strategies. Of all synthesized compounds, benzoxepine analogue 3-53 strongly inhibits tubulinpolymerization and shows excellent cytotoxicities against several human cancer cell lines.