β-Lactam type molecular scaffolds for antiproliferative activity: Synthesis and cytotoxic effects in breast cancer cells

Abstract

A series of novel b-lactam containing compounds are described as antiproliferative agents and potential selective modulators of the oestrogen receptor. The purpose of the study is to evaluate the antiproliferative effects of these compounds on human MCF-7 and MDA MB-231 breast cancer cells. The compounds are designed to contain three aryl ring substituents arranged on the heterocyclic azetidin-2-one (b-lactam), thus providing conformationally restrained analogues of the triarylethylene arrangement exemplified in the tamoxifen type structure. The compounds demonstrated potency in antiproliferative assays against MCF-7 human breast cancer cell line at low micromolar to nanomolar concentrations with low cytotoxicity and moderate binding affinity to the oestrogen receptor. The effect of a number of aryl and amine functional group substitutions on the antiproliferative activity of the b-lactam products was explored and a brief computational structure-activity relationship investigation with molecular simulation was investigated.

β-Lactam Estrogen Receptor Antagonists and a Dual-Targeting Estrogen Receptor/Tubulin Ligand

“…Compound 30 is structurally similar to our previously reported ER binding β-lactam 8 [ Figure 1, IC 50 =4.63 µM (MCF-7) 18 ], and the loss of activity indicates that the trimethoxy-substitution at N-1 is detrimental to ER binding affinity for this particular compound. The subsequent introduction of the basic pyrrolidine SERM-type ether substituent in 30 resulted in elimination of the ER binding activity from the core β-lactam structure of 26.…”

“…17 We have previously reported the antiproliferative activity of SERM-type compounds containing the β-lactam (azetidinone) scaffold with a basic side-chain which demonstrated antiestrogenic effects in MCF-7 cells (e.g. 18 As part of our ongoing interest in the development of ER ligands having novel scaffold structures we therefore decided to investigate a related series of β-lactams to identify potential lead compounds for further development as ERα or ERβ ligands. 18 As part of our ongoing interest in the development of ER ligands having novel scaffold structures we therefore decided to investigate a related series of β-lactams to identify potential lead compounds for further development as ERα or ERβ ligands.…”

“…Many tubulin binding compounds, such as paclitaxel and vinblastine, are in clinical use for various types of cancer. 18 The products were obtained as diastereomeric mixtures evident from the 1 H NMR spectra, e.g. [20][21][22] A large number of dual-ligands are progressing in clinical trials, including the novel drug conjugate trastuzumab emtansine (T-DM1) 6 involved synthesis of appropriately protected imines.…”

Synthesis and Evaluation of Azetidinone Analogues of Combretastatin A-4 as Tubulin Targeting Agents

“…We have recently reported the potent antiproliferative activity of β-lactam-containing compounds which are unsubstituted at C-3 or contain methyl substituent(s) at C-3 35 . We have also reported antiproliferative and antiestrogenic activity of compounds containing the β-lactam scaffold in MCF-7 cells 36 . In continuation of our earlier work, a further panel of compounds containing the β-lactam ring were examined as potential tubulin targeting agents.…”

Development of the β-lactam type molecular scaffold for selective estrogen receptor α modulator action: synthesis and cytotoxic effects in MCF-7 breast cancer cells

“…In a study to discover subtype selective ER scaffolds, we have identified a novel estrogen receptor modulator scaffold structure containing the b-lactam ring as a potential scaffold for SERMs, and have reported the antiproliferative effects and ER-binding properties of a series of 1,4-diarylsubstituted azetidin-2-ones, where the required basic amine function was positioned on the benzylic substituent at the C-3 position 32,40 . We now report the further investigation of this novel heterocyclic core scaffold structure as ER subtype selective ligands and the subsequent synthesis of a number of structurally varied b-lactam compounds, which are substituted at N-1, C-3 and C-4 with the required aryl rings.…”