All benzamides shown in are more potent than vinblastine and those that bear an aryl electron-donating substituent, some of which constitute single heavy atom additions, improve the H-bond acceptor ability of the added amide carbonyl that in turn proportionally increase the measured tubulin binding affinity (not shown) and functional activity (). Finally, compounds in this series also displayed diminished off target activity (Pgp efflux) and diminished Pgp-derived resistance (IC50 ratio between isogenic Pgp-derived resistant and sensitive cell lines, 88-fold for vinblastine) that correlated with the increasing lipophilic character of the amide substituent. Here, single atom changes that simply increase lipophilic character (cLogP) were found to directly correlate with and diminish resistance derived from Pgp overexpression and drug efflux that limits vinblastine clinical use ().
N2 - Triclosan is a potent inhibitor of Toxoplasma gondii enoyl reductase (TgENR), which is an essential enzyme for parasite survival. In view of triclosan's poor druggability, which limits its therapeutic use, a new set of B-ring modified analogs were designed to optimize its physico-chemical properties. These derivatives were synthesized and evaluated by in vitro assay and TgENR enzyme assay. Some analogs display improved solubility, permeability and a comparable MIC50 value to that of triclosan. Modeling of these inhibitors revealed the same overall binding mode with the enzyme as triclosan, but the B-ring modifications have additional interactions with the strongly conserved Asn130.
VHDL Design Representation and Synthesis / Edition 2 …
The synthesis of ketone IV (CI-TMI) incorporating the parent 1,2,7,7a-tetrahydrocycloprop[1,2-c]indol-4-one (CI) alkylation subunit of I is described and the results of its comparative evaluation (in vitro cytotoxic activity and DNA covalent alkylation properties) suggest that IV constitutes an agent bearing the min.
Nanocomposites: synthesis, structure, properties and …
cascades were used to directly introduce altered C4 substituents, providing the basis for concise total syntheses of a series of C4 modified vindolines and their subsequent single-step incorporation into the corresponding synthetic vinblastines in routes as short as 8-12 steps.
An OLED display can be driven ..
by total synthesis including both enantiomers of minovine, 4-desacetoxy-6,7-dihydrovindorosine, 4-desacetoxyvindorosine, and vindorosine as well as N-methylaspidospermidine.
This high flexibility in layer design, ..
reaction was implemented in the total synthesis of a series of alkaloids including (-)-vindoline, (-)-vindorosine, the closely related natural products (+)-4-desacetoxyvindoline and (+)-4-desacetoxyvindorosine, natural minovine, (+)-N-methylaspidospermidine, (+)-spegazzinine, (-)-aspidospermine, and a no.
Intel High Level Synthesis Compiler User Guide
Clear structure-activity relationships and a structural model were developed in the studies which provided many such 20' amides that exhibit substantial and some even remarkable enhancements in potency, many that exhibit further improvements in activity against a Pgp overexpressing resistant cancer cell line, and an important subset of the vinblastine analogs that display little or no differential in activity against a matched pair of vinblastine sensitive and resistant (Pgp overexpressing) cell lines.
High Level Synthesis Design Flow; ..
Extension of these studies provided a total synthesis of vincristine (II) via N-desmethylvinblastine (also a natural product), 16-desmethoxyvinblastine and 4-desacetoxy-16-desmethoxyvinblastine both of which we can now suggest are likely natural products produced by C.