N-Acyl 3-alkylidenyl- and 3-alkyl azetidin-2-ones: A new class of monocyclic .BETA.-lactam antibacterial agents. 1. Structure-activity relationships of 3-isopropylidene and 3-isopropyl analogs.

Abstract

The synthesis and antibacterial activity of a series of 7V-acyl 3-isopropylidenyl-and 3-isopropyl 2-azetidinones having potent in vitro antibacterial activity, particularly against anaerobic organisms, is described. A distinguishing structural feature of these compounds is the lack of any ionizable moiety appendant to the lactam nitrogen. 213In our search for novel synthetic antibacterial agents, we sought to explore the potential utility of a monocyclic /Mactam doubly-activated by an exocyclic C-C double bond at position C-3, and an appropriate electron-withdrawing moiety on the lactam N-l nitrogen. The rationale behind this template design hinged on the rudimentary concept of creating additional ring strain through the juxtapositioning of two sp2-hybridized carbons within the 4-membered ring. It was envisioned that such ring strain, in concert with the electron-withdrawing effect of an appropriate N-l substituent, might serve to sufficiently activate the /Mactam carbonyl as an electrophile, thereby potentially allowing for acylation of an active site serine hydroxyl in the targeted transpeptidases involved in microbial cell wall biosynthesis.4'5) The provision of a sufficient chemical reactivity to any particular /Mactam carbonyl does not, however, in and of itself render antibacterial activity.6'7) The /Mactam must also be fitted with appropriate structural appendages that allow for, or facilitate the binding of, the electrophile at the active site.8)9) In order to address this regard, at the outset of this lead-finding program we selected for synthesis both the Z and E isomers of 3-(l-methyl-2-hydroxyethylidene)-2-azetidinone10) (the latter comprising the lactam portion of the carbapenem asparenomycins).1 1>12) Such hydroxyisopropylidenyl templates, equipped with a readily manipulable synthetic handle, could be exploited to generate a multitude of structurally-varied entities at C-3, with the objective of optimization of biological activity. Subsequently we discovered that the "parent" 7V-acyl C-3 unsubstituted isopropylidenes (a, Schemes 1 and 2) and their corresponding dihydro analogs, the 7V-acyl 3-isopropyl azetidin-2-ones (b), exhibited the highest potencies of this class. Here we report on the structure-activity relationships (SAR) of these unusual /Mactam antibacterial agents.Results and Discussion Chemistry Wehave previously described the chemistry employed in the synthesis of the requisite 3-isopropylidenylThe content of this paper has been presented in part, see references 1~3.

Single Nucleotide Polymorphisms of EXOC1, BCL2, CCAT2, and CARD8 Genes and Susceptibility to Cervical Cancer in the Northern Chinese Han Population

“…This also explains why the prognostic significance of BCL2 expression depends on the type of cancer. Studies have shown that HPV E6 oncogenic protein is related to a variety of apoptosis regulators, such as BCL2 (48,49). In the unit point analysis of this study, the rs2270115 located in the BCL2 gene did not show a significant association with CC.…”

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“…Methyl Pentenoates (3). The compounds labeled as 3 consist of a mixture of methyl pent-3-enoate (mixture of E and Z isomers), methyl pent-4-enoate, and traces of methyl pent-2-enoate.…”

“…For example, if R′ = CH 3 , the resulting 4-methoxy-butanoyl- and 5-methoxy-pentanoyl- moieties are fragments of biologically active molecules, such as antibiotics, , prostaglandins and their antagonists, − analgesics, bronchodilators, , antiarrhythmics, and flavorings . In addition, alkoxyesters derived by ring-opening of GVL such as the ones depicted in Scheme have stimulated interest as bio-oxygenated solvents; while GVL-derived pentenoates have been considered as synthons for monomers. , …”