163810-26-2Relevant articles and documents
Structural Revision of Baulamycin A and Structure-Activity Relationships of Baulamycin A Derivatives
Sengupta, Sandip,Bae, Munhyung,Oh, Dong-Chan,Dash, Uttam,Kim, Hak Joong,Song, Woon Young,Shin, Injae,Sim, Taebo
, p. 12947 - 12966 (2017)
Total synthesis of the proposed structure of baulamycin A was performed. The spectral properties of the synthetic compound differ from those reported for the natural product. On the basis of comprehensive NMR study, we proposed two other possible structur
Design, synthesis, and evaluation of cystargolide-based β-lactones as potent proteasome inhibitors
Niroula, Doleshwar,Hallada, Liam P.,Le Chapelain, Camille,Ganegamage, Susantha K.,Dotson, Devon,Rogelj, Snezna,Groll, Michael,Tello-Aburto, Rodolfo
, p. 962 - 977 (2018/09/04)
The peptidic β-lactone proteasome inhibitors (PIs) cystargolides A and B were used to conduct structure-activity relationship (SAR) studies in order to assess their anticancer potential. A total of 24 different analogs were designed, synthesized and evaluated for proteasome inhibition, for cytotoxicity towards several cancer cell lines, and for their ability to enter intact cells. X-ray crystallographic analysis and subunit selectivity was used to determine the specific subunit binding associated with the structural modification of the β-lactone (P1), peptidic core, (Px and Py), and end-cap (Pz) of our scaffold. The cystargolide derivative 5k, structurally unique at both Py and P1, exhibited the most promising inhibitory activity for the β5 subunit of human proteasomes (IC50 = 3.1 nM) and significant cytotoxicity towards MCF-7 (IC50 = 416 nM), MDA-MB-231 (IC50 = 74 nM) and RPMI 8226 (IC50 = 41 nM) cancer cell lines. Cellular infiltration assays revealed that minor structural modifications have significant effects on the ability of our PIs to inhibit intracellular proteasomes, and we identified 5k as a promising candidate for continued therapeutic studies. Our novel drug lead 5k is a more potent proteasome inhibitor than carfilzomib with mid-to-low nanomolar IC50 measurements and it is cytotoxic against multiple cancer cell lines at levels approaching those of carfilzomib.
Design and synthesis of the stabilized analogs of belactosin A with the unnatural cis-cyclopropane structure
Kawamura, Shuhei,Unno, Yuka,Asai, Akira,Arisawa, Mitsuhiro,Shuto, Satoshi
supporting information, p. 6615 - 6622 (2013/09/24)
The belactosin A analog 2a, having the unnatural cis-cyclopropane structure instead of the trans-cyclopropane structure in belactosin A, is a much more potent proteasome inhibitor than belactosin A. However, its cell growth inhibitory effect is rather lower than that expected from its remarkable proteasome inhibitory effect, probably due to its instability under cellular conditions. We hypothesized that the instability of 2a was due to chemical and enzymatic hydrolysis of the strained β-lactone moiety. Thus, to increase the stability of 2a by chemical modification, its analogs with a sterically more hindered β-lactone moiety and/or cyclopropylic strain-based conformational restriction were designed and synthesized, resulting in the identification of a stabilized analog 6a as a proteasome inhibitor with cell growth inhibitory effects. Our findings suggest that the chemical and biological stability of 2a is significantly affected by the steric hindrance around its β-lactone carbonyl moiety and the conformational flexibility of the molecule.
The stereoselective total synthesis of (-)-dihydrotetrabenazine
Siva Senkar Reddy,Srinivas Reddy,Yadav,Subba Reddy
, p. 6916 - 6918 (2013/01/15)
A highly stereoselective synthesis of (-)-dihydrotetrabenazine has been accomplished using (R)-tert-butanesulfinamide as a chiral source. The synthesis involves the allylation of chiral N-sulfinyl imine followed by ring closure of the resulting secondary amide with a tethered halide and the Evans-Aldol reaction as key steps.
Fluoroalkenes as peptide isosteres: Ground state analog inhibitors of thermolysin
Bartlett,Otake
, p. 3107 - 3111 (2007/10/02)
Tripeptide analogs of the form Cbz-GlyΨ[(Z/-CF=CH]LeuXaa (1, Xaa = Gly, Ala, Leu, Phe, and NH2) were synthesized to assess the ability of the fluoroalkene moiety to mimic a peptide linkage. These compounds are modest inhibitors of the zinc endo