A novel and efficient Cu(I)-catalyzed ligand- and base-free multipathway domino strategy has been developed for the synthesis of 2-substituted quinazolinones. The reaction utilizes 2-bromobenzamide and multiform substrates such as aldehydes, alcohols, and methyl arenes for a one-pot protocol, whereas TMSN3 is used as a nitrogen source. A wide range of substrate scope, functional group tolerance, and operational simplicity are synthetically useful features.
The preparation of four per-O-benzyl-D-or Lglycero-D-galacto and D-or L-glycero-D-gluco heptopyranosyl sulfoxides and the influence of their side-chain conformations on reactivity and stereoselectivity in glycosylation reactions are described. The side-chain conformation in these donors is determined by the relative configuration of its point of attachment to the pyranoside ring and the two flanking centers in agreement with a recent model. In the D-and L-glycero-D-galacto glycosyl donors, the D-glycero-D-galacto isomer with the more electronwithdrawing trans,gauche conformation of its side chain was the more equatorially selective isomer. In the D-and L-glycero-D-gluco glycosyl donors, the L-glycero-D-gluco isomer with the least disarming gauche,gauche side-chain conformation was the most equatorially selective donor. Variable temperature NMR studies, while supporting the formation of intermediate glycosyl triflates at −80 °C in all cases, were inconclusive owing to a change in the decomposition mechanism with the change in configuration. It is suggested that the equatorial selectivity of the L-glycero-D-gluco isomer arises from H-bonding between the glycosyl acceptor and O6 of the donor, which is poised to deliver the acceptor antiperiplanar to the glycosyl triflate, resulting in a high degree of S N 2 character in the displacement reaction.
We describe the synthesis of 10-aza-9-oxakalkitoxin, an N,N,O-trisubstituted hydroxylamine-based analog, or hydroxalog, of the cytotoxic marine natural product kalkitoxin in which the -NMe-O-moiety replaces a -CHMe-CH 2 -unit in the backbone of the natural product. 10-Aza-9-oxakalkitoxin displays potent and selective cytotoxicity (IC 50 2.4 ng mL −1 ) comparable to that of kalkitoxin itself (IC 50 3.2 ng mL −1 ) against the human hepato-carcinoma cell line HepG2 over both the human leukemia cell line CEM and the normal hematopoietic CFU-GM. Like kalkitoxin, and contrary to the common expectation for hydroxylamines, 10-aza-9-oxakalkitoxin is not mutagenic.
A novel class of gallic acid based glycoconjugates were designed and synthesized as potential anticancer agents. Among all the compounds screened, compound 2a showed potent anticancer activity against breast cancer cells. The latter resulted in tubulin polymerization inhibition and induced G2/M cell cycle arrest, generation of reactive oxygen species, mitochondrial depolarization and subsequent apoptosis in breast cancer cells. In addition, ultraviolet-visible spectroscopy and fluorescence quenching studies of the compound with tubulin confirmed direct interaction of compounds with tubulin. Molecular modeling studies revealed that it binds at the colchicine binding site in tubulin. Further, 2a also exhibited potent in vivo anticancer activity in LA-7 syngeneic rat mammary tumor model. Current data projects its strong candidature to be developed as anticancer agent.
Over the last 20 years, both severe acute respiratory syndrome coronavirus-1 and severe
acute respiratory syndrome coronavirus-2 have transmitted from animal hosts to humans
causing zoonotic outbreaks of severe disease. Both viruses originate from a group of
betacoronaviruses known as subgroup 2b. The emergence of two dangerous human pathogens
from this group along with previous studies illustrating the potential of other subgroup
2b members to transmit to humans has underscored the need for antiviral development
against them. Coronaviruses modify the host innate immune response in part through the
reversal of ubiquitination and ISGylation with their papain-like protease (PLpro). To
identify unique or overarching subgroup 2b structural features or enzymatic biases, the
PLpro from a subgroup 2b bat coronavirus, BtSCoV-Rf1.2004, was biochemically and
structurally evaluated. This evaluation revealed that PLpros from subgroup 2b
coronaviruses have narrow substrate specificity for K48 polyubiquitin and ISG15
originating from certain species. The PLpro of BtSCoV-Rf1.2004 was used as a tool
alongside PLpro of CoV-1 and CoV-2 to design 30 novel noncovalent drug-like pan subgroup
2b PLpro inhibitors that included determining the effects of using previously unexplored
core linkers within these compounds. Two crystal structures of BtSCoV-Rf1.2004 PLpro
bound to these inhibitors aided in compound design as well as shared structural features
among subgroup 2b proteases. Screening of these three subgroup 2b PLpros against this
novel set of inhibitors along with cytotoxicity studies provide new directions for
pan-coronavirus subgroup 2b antiviral development of PLpro inhibitors.
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