Gallic acid-based indanone derivatives as anticancer agents q Hari Om Saxena a , Uzma Faridi b , Suchita Srivastava b , J. K. Kumar b , M. P. Darokar b , Suaib Luqman b , C. S. Chanotiya b , Vinay Krishna b , Arvind S. Negi b, * , S. P. S. Khanuja b a Rain Forest Research Institute, Jorhat, India b Central Institute of Medicinal and Aromatic Plants (CIMAP), PO CIMAP, Kukrail Road, Lucknow 226 015, India article info Article history: Received 28 March 2008 Revised 15 May 2008 Accepted 11 June 2008 Available online 14 June 2008 Keywords: Gallic acid Indanones Anticancer Osmotic fragility HMQC abstract Gallic acid-based indanone derivatives have been synthesised. Some of the indanones showed very good anticancer activity in MTT assay. Compounds 10, 11, 12 and 14 possessed potent anticancer activity against various human cancer cell lines. The most potent indanone (10, IC 50 = 2.2 lM), against MCF-7, that is, hormone-dependent breast cancer cell line, showed no toxicity to human erythrocytes even at higher concentrations (100 lg/ml, 258 lM). While, indanones 11, 12 and 14 showed toxicities to erythrocytes at higher concentrations. Ó 2008 Elsevier Ltd. All rights reserved. Indanones and related compounds are important bioactive mol- ecules. These compounds have been studied for various biological activities including cancer and Alzheimer’s type of diseases. Inda- nones are also used as drug intermediates, ligands of olefinic poly- merisation catalysts 2a,b and discotic liquid crystals. 3 Indanocine (1, Fig. 1) and its analogues are being developed to combat drug-resis- tant malignancies. 4 Another indanone analogue Donepezil hydro- chloride (2, Fig. 1) has been approved by US-FDA for the treatment of mild to moderate Alzheimer’s disease. This drug acts as an AChE (Acetylcholinesterase) inhibitor. 5 Dilemmaone A 6 (3, Fig. 1) and some other indanones have been isolated from natural products. Being such a useful moiety, several synthetic strategies have also been developed for their synthesis. 7a–j In continuation of our studies on modification of plant pheno- lics, 8a–e we modified gallic acid to an indanone moiety (4, Fig. 1). Gallic acid (5), a plant phenolic acid is present as hydrolysable tannins in almost all woody perennials. The modified gallic acid moiety i.e., a 3,4,5-trimethoxy phenyl unit has been established as an essential structural requirement for several anticancer leads 9 like Combretastatin A4, Podophyllotoxin, Colchicine, etc. (Fig. 2). In the present letter, gallic acid-based indanone derivatives have been synthesised and evaluated for their anticancer activity. One of the potent indanone (10) has further been modified to establish its structure and activity relationship (SAR). All the compounds show- ing potent anticancer activity were further evaluated for toxicity to human erythrocytes by performing erythrocyte fragility test. The synthetic strategy was as depicted in Scheme 1, gallic acid (5) was taken as the starting material. It was fully methylated at phenolic as well as carboxylic acid positions by refluxing it with di- methyl sulphate in 20% aqueous alkali to get 3,4,5-trimethyl gallic acid methyl ester (6) in 60% yield. The ester 6 underwent Grignard reaction with methylmagnesium iodide to yield the desired sub- strate 3,4,5-trimethoxyacetophenone (7). The acetophenone 7 and aldehyde 8 were condensed together in 3% aqueous methano- lic sodium hydroxide to get a corresponding chalcone 10 (9). Simi- larly, other aldehydes were condensed with 7 to get respective chalcones first and then modified to corresponding indanones (11–14). 11,12 All these chalcones were further modified to corre- sponding indanones by heating with trifluoroacetic acid in a sealed glass tube (Borosil). 13a However, indanone 15 was obtained on condensation of 3,4-dimethoxyacetophenone with 8 to get the respective chalcone and further modified to corresponding inda- none (15) as described for other indanones (11–14). Chalcones lacking an electron releasing groups in the phenyl ring of benzoyl group did not undergo Nazarov’s cyclisation reaction, due to deac- tivation by the carbonyl group. Therefore, chalcones synthesised from simple acetophenones could not be transformed into inda- nones. All the compounds were characterised by spectroscopic means. 17 All these indanones were evaluated for in vitro anticancer activity by MTT assay 14 (Table 1) against various human cancer 0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2008.06.039 q See Ref. 1. * Corresponding author. Tel.: +91 522 2717529x327; fax: +91 522 2342666. E-mail address: arvindcimap@rediffmail.com (A.S. Negi). Bioorganic & Medicinal Chemistry Letters 18 (2008) 3914–3918 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl