Original article Design, synthesis and QSAR studies of dispiroindole derivatives as new antiproliferative agents Riham F. George a , Nasser S.M. Ismail b , Jacek Stawinski c, ** , Adel S. Girgis d, * a Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt b Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt c Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-10691 Stockholm, Sweden d Pesticide Chemistry Department, National Research Centre, Dokki, Cairo 12622, Egypt article info Article history: Received 3 May 2013 Received in revised form 9 July 2013 Accepted 19 July 2013 Available online 11 August 2013 Keywords: 2,6-Bis(arylidene)-1-cyclohexanone Spiropyrrolidine-oxindole Azomethine ylide Antitumor QSAR abstract A variety of 4 0 -aryl-3-(arylmethylidene)-1 00 -[(cyclic-amino)methylene]-1 0 -methyl-dispiro[cyclohexane- 1,3 0 -pyrrolidine-2 0 ,3 00 -[3H]indole]-2,2 00 (1 00 H)-diones 4aeu were prepared via reaction of 2E,6E-bis(ar- ylidene)-1-cyclohexanones 1aei with azomethine ylides, generated in situ via a decarboxylative condensation of isatins 2aec and sarcosine (3). Single crystal X-ray study of 4a, revealed structural and stereochemical features of these derivatives. While most of the synthesized compounds exhibit mild antitumor properties when tested against various human tumor cell lines (HEPG2 “liver”, HELA “cervical” and PC3 “prostate” cancers), three of them, 4d and 4p (active against HEPG2), and compound 4g (active against HELA), demonstrated higher activities, that were close or even higher than that of the reference standard Doxorubicin. QSAR studies revealed good predictive and statistically significant 3 descriptor models (r 2 ¼ 0.903e0.812, r 2 adjusted ¼ 0.855e0.672, r 2 prediction ¼ 0.773e0.605). Ó 2013 Elsevier Masson SAS. All rights reserved. 1. Introduction Cancer represents one of the most serious clinical problems in the world and its incidence is rising in developing as well as in the developed countries. Despite improved imaging and molecular diagnostic techniques, and advances in prevention and chemo- therapeutic management, the disease still affects many millions of patients worldwide [1,2]. Apart from surgical treatment and irra- diation techniques, chemotherapy still remains an important op- tion for cancer therapy. Cancer cells are characterized by unlimited replications, self- sufficiency in growth signals, and insensitivity to antigrowth sig- nals, sustained angiogenesis, metastasis, and evasion of apoptosis [3]. Unfortunately, anticancer agents generally act on metabolically active or rapidly proliferating cells, and cannot distinguish effi- ciently between cancer and normal cells. Due to usually high toxicity and poor tolerance of the current anticancer agents [4], quest for novel agents with high efficiency, low toxicity, and minimum undesirable side effects is the major imperative of the contemporary drug development research [1]. The most promising new class of heterocyclic molecules having many interesting activity profiles and well-tolerated in human subjects [5,6] are tyrosine kinase inhibitors with antiangiogenic properties [7] bearing a 2-oxindole skeleton as in SU-5416 (sem- axanib) I and SU-11248 (sunitinib) II (Fig. 1). A structurally related compound SU9516 III was also reported as a potential inhibitor of cyclic-dependent kinases (CDKs) that can induce apoptosis in colon carcinoma cells [8]. Other important synthetic targets that attrac- ted great attention of many investigators in the last two decades are 2-oxindole analogs with spiropyrrolidine-oxindole structural motif [9]. This framework forms a core structure of many alkaloid and natural products exhibiting potent biological properties [10e13]. The simplest spiropyrrolidine-oxindole found in nature, coeru- lescine IV, displays a local anesthetic effect [14,15], while horsfiline V [16e21] (isolated from Horsfieldia superba) and elacomine VI [22] (isolated from Elaeagnus commutate) find use as indigenous medi- cine. Another members of this family, alstonisine VII, a natural alkaloid, was firstly isolated from Alstonia muelleriana [23,24], and mitraphylline VIII, isolated from Uncaria tomentosa, possesses potent antitumor properties against human brain cancer cell lines, neuroblastoma SKN-BE (2) and malignant glioma GAMG [25]. More examples are provided by spirotryprostatins A IX and B X [26,27], * Corresponding author. Tel.: þ20 2 01220447199; fax: þ20 2 33370931. ** Corresponding author. Tel.: þ46 8 162485; fax: þ46 8 15 49 08. E-mail addresses: js@organ.su.se (J. Stawinski), girgisas10@yahoo.com, girgisas10@hotmail.com (A.S. Girgis). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ejmech.2013.07.035 European Journal of Medicinal Chemistry 68 (2013) 339e351