Design, synthesis, biological evaluation and cocrystal structures with tubulin of chiral β -lactam bridged combretastatin A-4 analogues as potent antitumor agents

3-Vinylazetidin-2-Ones: Synthesis, Antiproliferative and Tubulin Destabilizing Activity in MCF-7 and MDA-MB-231 Breast Cancer Cells

“…In the present study the potential interaction of our novel synthesised 3-vinyl-β-lactams with the colchicine binding site of tubulin, a series of docking calculations using MOE 2018.0101 [88] was undertaken on both the 3 S /4 R and 3 R /4 S enantiomers of the β–lactams 7s and 7t using the tubulin co-crystallised with DAMA-colchicine X-ray crystal structure (PDB entry 1SA0) [5]. Only results for the 3 S /4 R studies will be discussed as these stereoisomers were more highly ranked than the 3 R /4 S enantiomer and this is also supported by the crystallographic evidence [37,38]. The 3 S /4 R enantiomers of the hydroxyl 7s and amino 7t substituted analogues overlay their B-rings on the C-ring of DAMA-colchicine, collocate the trimethoxyphenyl substituents, overlap the 3-hydroxyl/amino groups on the DAMA-colchicine carbonyl oxygen atom and form HBA interactions with Lys β352 as shown in Figure 10B and 10C.…”

“…The X-ray structure of CA-4 co-crystallised with tubulin has been determined suggesting that cis -CA-4 inhibits tubulin polymerization by preventing the transition from curved to straight tubulin [49]. The X-ray structure of cis and trans stereoisomers of a 3-methyl-1,4-diarylazetidinone [87] co-crystallised with tubulin was reported by Zhou et al [37,38]. In the present study the potential interaction of our novel synthesised 3-vinyl-β-lactams with the colchicine binding site of tubulin, a series of docking calculations using MOE 2018.0101 [88] was undertaken on both the 3 S /4 R and 3 R /4 S enantiomers of the β–lactams 7s and 7t using the tubulin co-crystallised with DAMA-colchicine X-ray crystal structure (PDB entry 1SA0) [5].…”

“…Small molecule tubulin polymerization inhibitors have been reported in which the cis double bond of CA-4 has been replaced by various heterocycles such as furan [25], indole[26,27], imidazole [28], isoxazole [29], triazole [30], tetrazole [31], benzoxepine [32], pyrazole [33], pyridine [34], benzimidazole [35] and related heterocycles [36]. While β-lactam antibiotics have occupied a central role in the treatment of pathogenic bacteria, the antiproliferative activity of compounds containing the β-lactam (azetidin-2-one) ring has also been investigated [37,38,39,40,41,42]. The synthesis and antitumour activity of a number of chiral β-lactam bridged CA-4 analogues have been reported [37,38].…”

“…While β-lactam antibiotics have occupied a central role in the treatment of pathogenic bacteria, the antiproliferative activity of compounds containing the β-lactam (azetidin-2-one) ring has also been investigated [37,38,39,40,41,42]. The synthesis and antitumour activity of a number of chiral β-lactam bridged CA-4 analogues have been reported [37,38]. Additional impetus for research efforts on β-lactam chemistry has been provided by the use of β-lactams as synthetic intermediates in organic synthesis [43].…”

Synthesis and Antiproliferative Evaluation of 3-Chloroazetidin-2-ones with Antimitotic Activity: Heterocyclic Bridged Analogues of Combretastatin A-4

“…The anti-cancer activity of structurally diverse monocyclic β-lactam compounds has been previously reported [39][40][41][42][43][44][45][46]. Chiral azetidin-2-ones were designed as nonisomerisable CA-4 analogues disrupting tubulin polymerisation, inducing cellular apoptosis and suppressing angiogenesis [47][48][49]. 3-Hydroxy-1,4-diaryl-2-azetidinones induce apoptosis, with the activation of AMP-activated protein kinase (AMPK) in colon cancer [50], while 3-methoxy-β-lactams show a significant decrease in AKT kinase activity, a cell survival pathway identified in breast cancer [51].…”