1.Novel double prodrugs of the iron chelator N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED): Synthesis, characterization, and investigation of activation by chemical hydrolysis and oxidation.
Thiele NA1, Abboud KA2, Sloan KB3. Eur J Med Chem. 2016 Apr 14;118:193-207. doi: 10.1016/j.ejmech.2016.04.037. [Epub ahead of print]
The development of iron chelators suitable for the chronic treatment of diseases where iron accumulation and subsequent oxidative stress are implicated in disease pathogenesis is an active area of research. The clinical use of the strong chelator N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) and its alkyl ester prodrugs has been hindered by poor oral bioavailability and lack of conversion to the parent chelator, respectively. Here, we present novel double prodrugs of HBED that have the carboxylate and phenolate donors of HBED masked with carboxylate esters and boronic acids/esters, respectively. These double prodrugs were successfully synthesized as free bases (7a-f) or as dimesylate salts (8a-c,e), and were characterized by 1H, 13C, and 11B NMR; MP; MS; and elemental analysis. The crystal structure of 8a was solved. Three of the double prodrugs (8a-c) were selected for further investigation into their abilities to convert to HBED by stepwise hydrolysis and H2O2 oxidation.
2.Structure-activity relationship studies of new rifamycins containing l-amino acid esters as inhibitors of bacterial RNA polymerases.
Czerwonka D1, Domagalska J1, Pyta K1, Kubicka MM2, Pecyna P2, Gajecka M3, Przybylski P4. Eur J Med Chem. 2016 Mar 24;116:216-221. doi: 10.1016/j.ejmech.2016.03.061. [Epub ahead of print]
New rifamycins (1-12) combined with different l-amino acids, containing methyl, ethyl, tert-butyl and benzyl groups at the ester part, via amine linkage, were synthesized and their structures in solution were determined by spectroscopic FT-IR and 1D and 2D NMR methods as well as visualized by DFT calculations. Two types of rifamycin structures were detected in solution: a zwitterionic one with the transferred proton from O(8)H phenol to secondary N(38) atom and a pseudocyclic structure stabilized via formation of intramolecular H-bond within the protonated basic C(3)-substituent. The presence of these rifamycins' structures influenced physico-chemical (logP, solubility) parameters and antibacterial properties. The bulkiness at the ester substituent of new rifamycins containing aromatic l-amino acids was found to be an important factor, besides the solubility, to achieve relatively high antibacterial activity against reference S. epidermidis and reference S.
3.Enantioselective Alkylation of Amino Acid Derivatives Promoted by Cyclic Peptoids under Phase-Transfer Conditions.
Schettini R1, De Riccardis F1, Della Sala G1, Izzo I1. J Org Chem. 2016 Mar 18;81(6):2494-505. doi: 10.1021/acs.joc.6b00065. Epub 2016 Mar 8.
The effects of substituents and cavity size on catalytic efficiency of proline-rich cyclopeptoids under phase-transfer conditions were studied. High affinity constants (Ka) for the sodium and potassium cations, comparable to those reported for crown ethers, were observed for an alternated N-benzylglycine/l-proline hexameric cyclopeptoid. This compound was found to catalyze the alkylation of N-(diphenylmethylene)glycine cumyl ester in values of enantioselectivities comparable with those reported for the Cinchona alkaloid ammonium salts derivatives (83-96% ee), and with lower catalyst loading (1-2.5% mol), in the presence of a broad range of benzyl, allyl and alkyl halides.