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Table 1. IC 50 in µmol; Cell lines: HT29-Colon carcinoma, MDA-MB-A31-renal, NCI-ADR-MDR ovarian, OVCAR8-ovarian, MCF7-breast, H1299-lung carcinoma; na-not activeCompoundHT29MDA-MBA31NCI-ADR OVCAR8 MCF7 H12999-AA 2.9 1.1 1.8 5.2 1.5 8.51a 2.6 1.6 2.4 5.1 2.4 1.041b 6.6 2.7 na 1.2 2.4 na1c 2.8 na 50 9.8 2.4 na1d 1.8 11.7 na na 6.3 na2a 15 13 7.2 4.7 1.2 na2b 0.9 0.6 0.2 0.4 0.7 0.62c 0.8 0.4 50 2.5 0.3 0.92d 1 1.2 0.8 3.7 0.8 2.6Amsacrine 0.7 0.6 1.5 50 0.6 3final compounds. Thus, finding short and efficient solid phase organic synthesis (SPOS)methods for the rapid generation of new 9-AA core based compounds will greatly enhancetheir availability for examination in biological systems. We have previously demonstrated anew, highly-efficient, one-pot derivatization in solution of 9-AA at the 9-amine position bysimple reductive amination and S N Ar reactions yielding series of novel substituted N(9)-benzylaminoacridines and N(9)-anilinoacridines correspondingly [2]. This unique methodallows formation of aniline, and benzyl tethers with electron withdrawing (EW) groups on9-AA core. This is a difficult task to accomplish using traditional nucleophilic substitutionof the deactivated amines on 9-chloroacridines [3]. Recently, we developed a SPOSapproach to novel 9-AA derivatives and various mono- and bis-9-anilinoacridine peptidylsubstances [4] using Fmoc chemistry compatible protocol. Such synthetic strategy rapidlygenerates 9-AAs with variable spacer lengths and charged, polar or hydrophobic residues atdesired positions like in 1 and 2 (Scheme 1), which can increase binding affinity,conformation stability and/or biological activity. Notably, the CO 2 H on 2a after cleavagefrom acid sensitive resin (Cl-Trt resin) can act as an anchor for possible conjugation to thecarrier. The preliminary screening of representative 1 and 2 on several cancer cell lines(Table 1) exhibits an antiproliferative activity for all compounds in µmolar to sub-µmolarconcentrations, as compared to 9AA itself and Amsacrine. The differences in the sensitivityto the tested compounds were observed between these cell lines. This observation can beexplained in terms of SAR centered on the substitution pattern on the aniline moiety.Interestingly, our peptidyl 9-AnAs are significantly more stable in human plasma (t 1/2 =12h-36h) than Amsacrine (t 1/2 = 0.5h) and AHMA (t 1/2 = 1.5h) [5], pointing on possiblereduced toxicity than parent 9-AA drugs. Encouraged by this feasibility experiment, weproceeded to the massive rational drug design program based on our synthetic tools andassisted by extensively reported modeling data on 9-AAs and their peptidyl derivatives [6].Our current research is focused on the optimization and the mechanism of action studies ofthe recently discovered most promising sub-µmolar leads against lung carcinoma (H1299),relatively insensitive to chemotherapy.AcknowledgmentsWe wish to thank Dr. Hugo Gotlib from Bar Ilan University for analytical assistance.References1. Sebestík, J., et al. Curr. Prot. Pept. Sci. 8, 471-483 (2007).2. Gellerman, G., Gaisin, V., Brider, T. Tet. Lett. 51, 836-839 (2010).3. Guetzoyan, L., Ramiandrasoa, F., Perree-Fauvet, M. Bioorg. Med. Chem. 15, 3278-3289 (2007).4. He, Z., et al. Bioorg. Med. Chem. 16, 4390-4400 (2008).5. Tsann-Long, Su Cur. Med. Chem. 9, 1677-1688 (2002).6. Caffrey, C.R., et al. Antimicrobial Agents and Chemotherapy 51, 2164-2172 (2007).231