Short Communication SAR of Cu (II) Thiosemicarbazone Complexes as Hypoxic Imaging Agents: MM3 Analysis and Prediction of Biologic Properties Sweta Singh, 1,2 Anjani K. Tiwari, 1 Himanshu Ojha, 1 Nitin Kumar, 1 Bachcha Singh, 2 and Anil K. Mishra 1 Abstract Copper(II) bis(thiosemicarbazone) are very useful for blood flow and hypoxic imaging. The aim of this study was to identify structure-activity relationships (SARs) within a series of analogues with different substitution patterns in the ligands, in order to design improved hypoxia imaging agents and elucidate hypoxia selectivity mechanisms. Genetic algorithms (GAs) were used to develop specific copper metal-ligand force field parameters for the MM3 force-field calculations. These new parameters produced results in good agreement with experiment and previ- ously reported copper metal-ligand parameters. A successful quantitative SAR (QSAR) for predicting the several classes of Cu(II)-chelating ligands was built using a training set of 21 Cu(II) complexes. The QSAR exhibited a correlation between the predicted and experimental test set. The QSAR preformed with great accuracy; r 2 ¼ 0.95 and q 2 ¼ 0.90 utilizing a leave-one-out cross-validation with multiple linear regression analysis to find correlation between different calculated molecular descriptors of these complexes. The final QSAR mathematical models were found as the following: QSAR model for copper(II) bis(thiosemicarbazone) Log P = f3.01698 ( – 0.0590)g - LUMO f0.1248 ( – 0.068)g + MR f0.3219 ( – 0.086)g n ¼ 21 jrj¼ 0:972 s ¼ 0:188 F ¼ 98:102 The resulting models could act as an efficient strategy for estimating the hypoxic conditions through imaging and provide some insights into the structural features related to the biological activity of these compounds. Key words: QSAR, linear regression, chelating agent, imaging, genetic algorithms Introduction S everal semicarbazones, as well as their sulphur an- alogs, have proved the efficiency and efficacy in combat- ing various diseases. 1 It is of great interest because of their chemistry and, potentially, beneficial biologic activi- ties, such as antitumor, -bacterial, -viral, and -malarial ac- tivities. 2–4 One of the important aspect of these compounds are that Cu(II) bis(thiosemicarbazone) complexes have been used in vivo as radiotracers for the evaluation of blood flow in various organs, such as the brain, kidneys, and heart, as well as for the evaluation of hypoxia in tissue. 5–7 We have been developing an approach, based on redox- active copper complexes, 8–13 following the demonstration that the copper complex of bis(thiosemicarbazone) is selec- tively taken up in hypoxic tissue. 14 These complexes have a number of interesting properties and uses and have been in- vestigated for their potential in anticancer chemotherapy, 15 superoxide dismutase–like activity, 16 and in radiolabeled form as nontissue selective blood-perfusion tracers. 17 They diffuse into cells because of its low molecular weight, pla- narity, 18,19 and lipophilicity. 20 It then becomes trapped by intracellular reduction to a copper (I) complex, 21 followed by dissociation and entry of the copper into the normal intra- cellular copper pool. 22 1 Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India. 2 Division of Chemistry, Benares Hindu University, Varansi, India. Address correspondence to: Anil K. Mishra; Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences; Brig. S.K. Mazumdar Road, Timarpur, Delhi 110054, India E-mail: mis_ak@rediffmail.com CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS Volume 25, Number 1, 2010 ª Mary Ann Liebert, Inc. DOI: 10.1089=cbr.2009.0670 117