91088-80-1Relevant academic research and scientific papers
Environmentally Friendly SPPS II: Scope of Green Fmoc Removal Protocol Using NaOH and Its Application for Synthesis of Commercial Drug Triptorelin
P?ibylka, Adam,Krchňák, Viktor,Schütznerová, Eva
, p. 8798 - 8811 (2020)
With the growing necessity to consider environmental impacts when synthesizing peptide-based drugs and to expand upon the recently published short communication report, we herein present a thorough evaluation of a green Fmoc removal protocol. Our protocol avoids the use of hazardous components (using piperidine as a base and dichloromethane (DCM) and N,N-dimethylformamide (DMF) as solvents) and relies on the utilization of the green mineral base NaOH in combination with the greener solvent 2-methyltetrahydrofuran (2-MeTHF) mixed with MeOH. For the original Fmoc removal cocktail (solvents ratio of 1:1), we evaluated the impact of quality/purity of the used 2-MeTHF, scale-up, ratio of 2-MeTHF/MeOH, utilized hydroxide, temperature, and reaction time. An alternative 3:1 protocol was examined using various amino acids, and only Gly required the optimization of the Fmoc removal cocktail composition. The optimized protocol used to remove Fmoc from Gly residue was proved by the synthesis of Leu-enkephalin. We also investigated the stability of the conventional amino acid side-chain-protecting groups, t-Bu, Boc, Trt, and Pbf, and the formation of aspartimide as an undesirable side reaction that occurs during Fmoc solid-phase peptide synthesis (SPPS). The applicability of this synthesis strategy was documented by evaluating the SPPS of a commercial drug used for prostate and breast cancer treatments - decapeptide triptorelin.
N-Substituted Glutamyl Sulfonamides as Inhibitors of Glutamate Carboxypeptidase II (GCP2)
Blank, Brian R.,Alayoglu, Pinar,Engen, William,Choi, Joseph K.,Berkman, Clifford E.,Anderson, Marc O.
experimental part, p. 241 - 247 (2012/01/12)
Glutamate carboxypeptidase II (GCP2) is a membrane-bound cell-surface peptidase which is implicated in several neurological disorders and is also over-expressed in prostate tumor cells. There is a significant interest in the inhibition of GCP2 as a means of neuroprotection, while GCP2 inhibition as a method to treat prostate cancer remains a topic of further investigation. The key zinc-binding functional group of the well-characterized classes of GCP2 inhibitors (phosphonates and phosphoramidates) is tetrahedral and negatively charged at neutral pH, while glutamyl urea class of inhibitors possesses a planar and neutral zinc-binding group. This study introduces a new class of GCP2 inhibitors, N-substituted glutamyl sulfonamides, which possess a neutral tetrahedral zinc-binding motif. A library containing 15 secondary sulfonamides and 4 tertiary (N-methyl) sulfonamides was prepared and evaluated for inhibitory potency against purified GCP2 enzyme activity. While most inhibitors lacked potency at 100μm, short alkyl sulfonamides exhibited promising low micromolar potency, with the optimal inhibitor in this series being glutamyl N-(propylsulfonamide) (2g). Lastly, molecular docking was used to develop a model to formulate an explanation for the relative inhibitory potencies employed for this class of inhibitors. A small library of glutamyl sulfonamides was prepared and evaluated for in vitro potency against glutamate carboxypeptidase II (GCP2). Short alkyl sulfonamide inhibitors were the most potent, demonstrating low micromolar IC50 values.
