1079307-01-9Relevant academic research and scientific papers
Macrocyclic Peptides that Selectively Inhibit the Mycobacterium tuberculosis Proteasome
Zhang, Hao,Hsu, Hao-Chi,Kahne, Shoshanna C.,Hara, Ryoma,Zhan, Wenhu,Jiang, Xiuju,Burns-Huang, Kristin,Ouellette, Tierra,Imaeda, Toshihiro,Okamoto, Rei,Kawasaki, Masanori,Michino, Mayako,Wong, Tzu-Tshin,Toita, Akinori,Yukawa, Takafumi,Moraca, Francesca,Vendome, Jeremie,Saha, Priya,Sato, Kenjiro,Aso, Kazuyoshi,Ginn, John,Meinke, Peter T.,Foley, Michael,Nathan, Carl F.,Darwin, K. Heran,Li, Huilin,Lin, Gang
supporting information, p. 6262 - 6272 (2021/05/29)
Treatment of tuberculosis (TB) currently takes at least 6 months. Latent Mycobacterium tuberculosis (Mtb) is phenotypically tolerant to most anti-TB drugs. A key hypothesis is that drugs that kill nonreplicating (NR) Mtb may shorten treatment when used in combination with conventional drugs. The Mtb proteasome (Mtb20S) could be such a target because its pharmacological inhibition kills NR Mtb and its genetic deletion renders Mtb unable to persist in mice. Here, we report a series of macrocyclic peptides that potently and selectively target the Mtb20S over human proteasomes, including macrocycle 6. The cocrystal structure of macrocycle 6 with Mtb20S revealed structural bases for the species selectivity. Inhibition of 20S within Mtb by 6 dose dependently led to the accumulation of Pup-tagged GFP that is degradable but resistant to depupylation and death of nonreplicating Mtb under nitrosative stress. These results suggest that compounds of this class have the potential to develop as anti-TB therapeutics.
Esterase-sensitive prodrugs of a potent bisubstrate inhibitor of nicotinamide n-methyltransferase (Nnmt) display cellular activity
van Haren, Matthijs J.,Gao, Yongzhi,Buijs, Ned,Campagna, Roberto,Sartini, Davide,Emanuelli, Monica,Mateuszuk, Lukasz,Kij, Agnieszka,Chlopicki, Stefan,de Castilla, Pol Escudé Martinez,Schiffelers, Raymond,Martin, Nathaniel I.
, (2021/09/16)
A recently discovered bisubstrate inhibitor of Nicotinamide N-methyltransferase (NNMT) was found to be highly potent in biochemical assays with a single digit nanomolar IC50 value but lacking in cellular activity. We, here, report a prodrug strategy designed to translate the observed potent biochemical inhibitory activity of this inhibitor into strong cellular activity. This prodrug strategy relies on the temporary protection of the amine and carboxylic acid moieties of the highly polar amino acid side chain present in the bisubstrate inhibitor. The modification of the carboxylic acid into a range of esters in the absence or presence of a trimethyl-lock (TML) amine protecting group yielded a range of candidate prodrugs. Based on the stability in an aqueous buffer, and the confirmed esterase-dependent conversion to the parent compound, the isopropyl ester was selected as the preferred acid prodrug. The isopropyl ester and isopropyl ester-TML prodrugs exhibit improved cell permeability, which also translates to significantly enhanced cellular activity as established using assays designed to measure the enzymatic activity of NNMT in live cells.
One-pot synthesis of Weinreb amides employing 3,3-dichloro-1,2-diphenylcyclopropene (CPI-Cl) as a chlorinating agent
Shekharappa,Roopesh Kumar,Sureshbabu, Vommina V.
, p. 790 - 798 (2019/03/26)
The synthesis of Nα-protected amino alkyl Weinreb amides starting from the corresponding α-amino acids as well as carboxylic acids has been delineated through the in situ generation of acid chlorides using CPI-Cl as a chlorinating agent. The protocol is simple; the reaction conditions employed were mild, and compatible with all the three commonly used urethane protecting groups namely, Boc, Cbz and Fmoc groups. The resulting Weinreb amides are obtained in good yields as optically pure products.
Kinetic studies on the stability and reactivity of β-amino alkylzinc iodides derived from amino acids
Rilatt, Ian,Jackson, Richard F. W.
supporting information; experimental part, p. 8694 - 8704 (2009/04/11)
(Chemical Equation Presented) β-Amino alkylzinc iodides are intrinsically unstable toward β-elimination and protonation. The aim of this study was to determine the rates of these processes and also to understand how the reactivity of a range of β-amino alkylzinc iodides in Negishi cross-coupling reactions is influenced by the presence of functional groups within the zinc reagent. Decomposition of β-benzamido alkylzinc iodides occurs by protonation, and the first-order rate constant for the self-protonation of the carbon-zinc bond in reagent 4b was determined to be 5.2 × 10-6 s-1 (at 291 K). In contrast, the carbamate derivative 2 decomposes by a first-order elimination process. The homologous reagent 3, derived from glutamic acid, decomposes more quickly by β-elimination, with a first-order rate constant of 24 × 10 -6 s-1 (at 291 K). Reagents 23 and 25, in which the Boc group has been replaced with a trifluoroacetyl group, are more stable toward β-elimination than the corresponding reagents 2 and 3, a striking outcome given that the trifluoroacetamido group is a better leaving group. Moreover, this replacement also changes the mechanism of the elimination to a second order process. Pseudo-second-order rate constants for the Negishi cross-coupling of reagents 2, 3, 23, and 25 with iodobenzene have been determined, revealing the higher reactivity of the glutamic acid-derived reagents 3 and 25. The main factor influencing reactivity, therefore, is determined to be the proximity of the ester group, rather than the nature of the nitrogen protecting group. Finally, β-amino alkylzinc iodides 46-48 containing Weinreb amides have been prepared, rate constants for their decomposition through elimination determined, and their synthetic potential for the preparation of β-amino ketones established.
