Design, synthesis and antiproliferative activity of some 3-benzylidene-2,3-dihydro-1-benzopyran-4-ones which display selective toxicity for malignant cells

Abstract

A series of 3-benzylidene-4-chromanones 1a-l were prepared and their cytotoxicity towards human Molt 4/C8 and CEM T-lymphocytes as well as murine L1210 lymphoid leukemia cells were compared to the previously generated biodata in these three assays for the isosteric 2-benzylidene-1-tetralones 2a-l. Over 40% of the compounds in series 1 were more potent than their counterparts in series 2, while equipotency was noted in one-third of the comparisons made. In general the IC(50) values of 1a-l towards the human T-lymphocytes were in the low micromolar range. Molecular modelling revealed differences in shapes of representative molecules in series 1 and 2 which may contribute to the variation in cytotoxic potencies. Most of the compounds in series 1 displayed greater potencies towards HSC-2, HSC-3, HSC-4 and HL-60 neoplasms than HGF, HPC, and HPLF normal cells and were well tolerated in mice.

Quantitative Structure-cytotoxicity Relationship of 3-Benzylidenechromanones

“…It is urgent to explore the method by which this type of side-effect can be alleviated. We also found that the introduction of dimethylamino groups [6,12] and chloride [8] in the 4'-position of benzene ring produced comparable TS values with [3,10,15]. This indicates that molecular shape, size and polarization are useful for the evaluation of tumor-specificity of 3-benzylidenechromanone derivatives.…”

“…This may be a new type of side-effect induced by anticancer drugs. We found that compounds [6,8,16] showed much lower cytotoxicity against human normal keratinocytes as compared with DXR and 5-FU (Table II). It is urgent to explore the method by which this type of side-effect can be alleviated.…”

“…(3E)-2,3-Dihydro-3-(phenylmethylene)-4H-1-benzopyran-4-one [1], (3E)-2,3-dihydro-3-[(4-hydroxyphenyl) methylene]-4H-1-benzopyran-4-one [2], (3E)-2,3-dihydro-3-[(3,4-dihydroxyphenyl)methylene]-4H-1-benzopyran-4-one [3], (3E)-2,3-dihydro-3-[(4-methoxyphenyl)methylene]-4H-1-benzopyran-4-one [4], (3E)-2,3-dihydro-3-[(3,4-dimethoxyphenyl)methylene]-4H-1-benzopyran-4-one [5], (3E)-2,3-dihydro-3-[(4-dimethylaminophenyl)methylene]-4H-1-benzopyran-4-one [6], (3E)-2,3-dihydro-3-[(4-fluorophenyl)methylene]-4H-1-benzopyran-4-one [7], (3E)-3-[(4-chlorophenyl)methylene]-2,3-dihydro-4H-1-benzopyran-4-one [8], (3E)-2,3-dihydro-7-hydroxy-3-[(4-hydroxyphenyl)methylene]-4H-1-benzopyran-4-one [9], (3E)-2,3-dihydro-3-[(3,4-dihydroxyphenyl)methylene]-7-hydroxy-4H-1-benzopyran-4-one [10], (3E)-2,3-dihydro-7-hydroxy-3-[(4-methoxyphenyl)methylene]-4H-1-benzopyran-4-one [11], (3E)-2,3-dihydro-3-[(4-dimethylaminophenyl)methylene]-7-hydroxy-4H-1-benzopyran-4-one [12], (3E)-2,3-dihydro-7-methoxy-3-(phenylmethylene)-4H-1-benzopyran-4-one [13], (3E)-2,3-dihydro-3-[(4-hydroxyphenyl)methylene]-7-methoxy-4H-1-benzopyran-4-one [14], (3E)-2,3-dihydro-3-[(3,4-dihydroxyphenyl)methylene]-7-methoxy-4H-1-benzopyran-4-one [15], (3E)-2,3-dihydro-7-methoxy-3-[(4-methoxyphenyl)methylene]-4H-1-benzopyran-4-one [16] and (3E)-2,3-dihydro-3-[(4-dimethylaminophenyl)methylene]-7-methoxy-4H-1-benzopyran-4-one [17] (structures shown in Figure 1) were synthesized by base-catalyzed condensation of appropriate 4-chromanone with substituted benzaldehyde derivatives according to previous methods (19,20). All compounds were dissolved in DMSO at 40 mM and stored at -20˚C before use.…”

3-Benzylidene-4-chromanones: a novel cluster of anti-tubercular agents

“…The compounds in series 1 were prepared by a literature procedure 13 reported previously from our laboratory and the purity of the compounds was established by 1 H-NMR spectroscopy, melting points and elemental analyses while the synthesis of the analogs in series 2-5 has been described previously 14 .…”

“…Second, an ether oxygen atom was placed into the heterocyclic ring with a view to serving two purposes, namely, reducing the lipophilicity of the molecules and also having the capacity to assist the alignment of these compounds at a binding site by hydrogen bonding. Third, a previous study revealed that 1a-l displayed excellent cytotoxic properties towards several tumour cell lines and are well tolerated in mice 13 . As a part of our ongoing effort to develop novel anti-mycobacterial agents, the present investigation is focused on the evaluation of the antitubercular potential of 3-benzylidene-4-chromanones 1 and also to develop structure-activity relationships that would afford guidelines for expansion in this area of study.…”