11 research outputs found
Total Synthesis and Evaluation of c26-Hydroxyepothilone D Derivatives for Photoaffinity Labeling of β-Tubulin
Three photaffinity labeled derivatives of epothilone D were prepared by total synthesis, using efficient novel asymmetric synthesis methods for the preparation of two important synthetic building blocks. The key step for the asymmetric synthesis of (S,E)-3-(tert-butyldimethylsilyloxy)-4-methyl-5-(2-methylthiazol-4-yl)pent-4-enal involved a ketone reduction with (R)-Me-CBS-oxazaborolidine. For the synthesis of (5S)-5,7-di-[(tert-butyldimethylsilyl)oxy]-4,4-dimethylheptan-3-one an asymmetric Noyori reduction of a β-ketoester was employed. The C26 hydroxyepothilone D derivative was constructed following a well-established total synthesis strategy and the photoaffinity labels were attached to the C26 hydroxyl group. The photoaffinity analogues were tested in a tubulin assembly assay and for cytotoxicity against MCF-7 and HCT-116 cancer cell lines. The 3- and 4-azidobenzoic acid analogues were found to be as active as epothilone B in a tubulin assembly assay, but demonstrated significantly reduced cellular cytotoxicity compared to epothilone B. The benzophenone analogue was inactive in both assays. Docking and scoring studies were conducted that suggested that the azide analogues can bind to the epothilone binding site, but that the benzophenone analogue undergoes a sterically driven ligand rearrangement that interrupts all hydrogen bonding and therefore protein binding. Photoaffinity labeling studies with the 3-azidobenzoic acid derivative did not identify any covalently labeled peptide fragments, suggesting that the phenylazido side chain was predominantly solvent-exposed in the bound conformation
Total synthesis and evaluation of 22-(3-azidobenzoyloxy)methyl epothilone C for photoaffinity labeling of β-tubulin
The total synthesis of 22-(3-azidobenzoyloxy)methyl epothilone C is described as a potential photoaffinity probe to elucidate the β-tubulin binding site. A sequential Suzuki-aldol-Yamaguchi macrolactonization strategy was utilized employing a novel derivatized C1âC6 fragment. The C22-functionalized analog exhibited good activity in microtubule assembly assays, but cytotoxicity was significantly reduced. Molecular modeling simulations indicated that excessive steric bulk in the C22 position is accommodated by the large hydrophobic pocket of the binding site. Photoaffinity labeling studies were inconclusive suggesting non-specific labeling
Diastereoselective access to substituted 4-aminopiperidines via a pyridine reduction approach
We describe herein a diastereoselective approach to access substituted-4-aminopiperidines from pyridine precursors. This methodology has successfully been applied to synthesize 2-alkyl substrates as well as more complex molecular entities of interest to the pharmaceutical industry
Diastereoselective access to substituted 4-aminopiperidines via a pyridine reduction approach
We describe herein a diastereoselective approach to access substituted-4-aminopiperidines from pyridine precursors. This methodology has successfully been applied to synthesize 2-alkyl substrates as well as more complex molecular entities of interest to the pharmaceutical industry
1,2-Difunctionalized Bicyclo[1.1.1]pentanes: Long Sought After Bioisosteres for ortho/meta-Substituted Arenes
The development of a versatile platform for the synthesis of 1,2-difunctionalized bicyclo[1.1.1]pentanes to potentially mimic ortho/meta-substituted arenes is described. The synthesis of useful building blocks bearing alcohol, amine, and carboxylic acid functional handles has been achieved from a simple common intermediate. Several ortho and/or meta-substituted benzene analogues as well as simple molecular matched pairs have also been prepared using this platform. In-depth biological and computational studies are currently in progress to validate the ortho and/or meta-character of these new bioisosteres. Results of these investigations will be reported in due course.</p
Diastereoselective access to substituted 4-aminopiperidines via a pyridine reduction approach
Synthesis of Small 3âFluoro- and 3,3-Difluoropyrrolidines Using Azomethine Ylide Chemistry
Here,
we report accessing small 3-fluoropyrrolidines and 3,3-difluoropyrrolidines
through a 1,3-dipolar cycloaddition with a simple azomethine ylide
and a variety of vinyl fluorides and vinyl difluorides. We demonstrate
that vinyl fluorides within ι,β-unsaturated, styrenyl
and even enol ether systems can participate in the cycloaddition reaction.
The vinyl fluorides are relatively easy to synthesize through a variety
of methods, making the 3-fluoropyrrolidines very accessible
Total synthesis and evaluation of 22-(3-azidobenzoyloxy)methyl epothilone C for photoaffinity labeling of β-tubulin
Rapid Entry into the Cryptophycin Core via an Acyl-β-lactam Macrolactonization:â Total Synthesis of Cryptophycin-24
Discovery of <i>N</i>â((3<i>R</i>,4<i>R</i>)â4-Fluoro-1-(6-((3-methoxy-1-methylâ1<i>H</i>âpyrazol-4-yl)amino)-9-methylâ9<i>H</i>âpurin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild-Type EGFR
Mutant epidermal growth factor receptor
(EGFR) is a major driver
of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors,
such as erlotinib, effect a transient beneficial response in EGFR
mutant NSCLC patients before resistance mechanisms render these inhibitors
ineffective. Secondary oncogenic EGFR mutations account for approximately
50% of relapses, the most common being the gatekeeper T790M substitution
that renders existing therapies ineffective. The discovery of PF-06459988
(<b>1</b>), an irreversible pyrrolopyrimidine inhibitor of EGFR
T790M mutants, was recently disclosed. Herein, we describe our continued efforts to achieve potency across
EGFR oncogenic mutations and improved kinome selectivity, resulting
in the discovery of clinical candidate PF-06747775 (<b>21</b>), which provides potent EGFR activity against the four common mutants
(exon 19 deletion (Del), L858R, and double mutants T790M/L858R and
T790M/Del), selectivity over wild-type EGFR, and desirable ADME properties.
Compound <b>21</b> is currently being evaluated in phase-I clinical
trials of mutant EGFR driven NSCLC