- Design, synthesis, and evaluation of cystargolide-based β-lactones as potent proteasome inhibitors
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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.
- Niroula, Doleshwar,Hallada, Liam P.,Le Chapelain, Camille,Ganegamage, Susantha K.,Dotson, Devon,Rogelj, Snezna,Groll, Michael,Tello-Aburto, Rodolfo
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supporting information
p. 962 - 977
(2018/09/04)
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- Using peptidic inhibitors to systematically probe the S1′ site of caspase-3 and caspase-7
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(Chemical Equation Presented) Fifteen ketone-containing peptides were designed, synthesized, and used to probe the effect of substitution at the P1′ position on caspase-3 and -7 inhibition. Even with the large bias of Ac-Asp-Glu-Val-Asp at the P4-P1 positions, certain peptides with cyclic functionality in the P1′ position show a dramatically reduced ability to inhibit these caspases. Additionally, trends toward isozyme selectivity were also uncovered for particular P1′ substituents. The data indicate that substitution in the P1′ position can drastically affect both caspase inhibition and selectivity.
- Goode, David R.,Sharma, Anil K.,Hergenrother, Paul J.
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p. 3529 - 3532
(2007/10/03)
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- Allyl Esters as Selectively Removable Carboxy-protecting Functions in Peptide and N-Glycopeptide Syntheses
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Allyl esters are advantageous in protection of the carboxylic function in peptide and glycopeptide syntheses and can easily be synthesized from amino acids.They are stable under acidic conditions used for the removal of the Boc and Z groups.Under neutral or weakly basic conditions allyl esters are cleaved smoothly on treatment with catalytic amounts of tris(triphenylphosphane)rhodium(I) chloride in ethanol/water (9:1) leaving the N-protecting function and the N-glycosidic bond untouched.Selective deblocking of the α-carboxylic function of protected N-glycosylated asparagine derivatives 15 carried out in this way is exploited in C-terminal chain extension in the synthesis of N-glycotripeptides 17,e.g 17c, the latter representing a partial sequence of a human immunoglobulin G1.
- Waldmann, Herbert,Kunz, Horst
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p. 1712 - 1725
(2007/10/02)
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