CombinatorialSynthesis,LeadIdentification,andAntitumorStudyofa Chalcone-BasedPositional-ScanningLibrary by AhsanUllah a ), FarzanaLatifAnsari* a ), Ihsan-ul-Haq b ), SaminaNazir a ), and BushraMirza b ) a ) Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan (e-mail: fla_qau@yahoo.com) b ) Department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan A 175-member chalcone library was designed and synthesized from seven differently substituted acetophenones (A 1 – A 7 ) and 25 differently substituted aryl or heteroaryl aldehydes ( B 1 – B 25 ). Potential lead compounds were identified by deconvolution of a two-dimensional library matrix via positional scanning, and the members of the most-active sub-libraries were synthesized and screened against crown- gall tumors with the aid of the potato-disc assay. The resulting hits gave rise to significant antitumor activities, with no antibacterial effect on the tumor-producing bacterium Agrobacterium tumefaciens . Two identified lead structures, (2E)-3-(2-chlorophenyl)-1-phenylprop-2-en-1-one (A 1 B 9 ) and the hydroxy analogue (2E)-3-(2-chlorophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (A 2 B 9 ), are promising candi- dates to be developed into highly effective anticancer chemotherapeutics. Introduction. – Chalcones are medicinally important a,b-unsaturated ketones. Though structurally simple, they have displayed an impressive array of biological activities including antimalarial, antileishmanial, anti-asthmatic, anti-oxidant, antibac- terial, antifungal, anti-inflammatory, antitubercular, immunomodulatory, tyrosinase- inhibition, cholinesterase-inhibition, cytotoxic, antimitotic, anticancer, antiulcer, and hepatoprotective properties [1 – 15]. Some chalcones are used as medicines, while others are being investigated as drug candidates [16]. Despite the wide range of biological activities, relatively little has been reported so far on the antitumor properties of chalcones, with no reports on the inhibition of crown-gall tumor. Crown gall is a neoplastic disease of plants, which occurs in more than 60 families of dicotyledons and many gymnosperms. The causative agents of this disease are specific strains of the Gram-negative Agrobacterium tumefaciens . The relevance of the crown- gall-tumor system to the general cancer problem has been thoroughly reviewed [17 – 23] . The inhibition of crown-gall tumor induced by A. tumefaciens in potato-disc tissue is an assay based on antimitotic activity ; this assay is capable of detecting a broad range of known and novel antitumor effects. Crown gall causes the bulging of a mass of tissues from stems and roots of woody and herbaceous plants. These tumors may be spongy or hard, and may or may not have deleterious effects on the plant. Histologically, crown- gall tumors are similar to those found in humans and animals. During infection of plant material with A. tumefaciens , a tumor-producing plasmid, found in bacterial DNA, is incorporated in the chromosomal plant DNA. When plant tissue is wounded, it releases phenols and other compounds that activate the Ti-plasmid in A. tumefaciens. The Ti- plasmid causes the plant)s cells to multiply rapidly without going through apoptosis, CHEMISTRY & BIODIVERSITY – Vol. 4 (2007) 203 # 2007 Verlag Helvetica Chimica Acta AG, Zürich