Abstract
We designed, synthesized, and evaluated novel 2,6,9-trisubstituted purine derivatives for their prospective role as antitumor compounds. Using simple and efficient methodologies, 31 compounds were obtained. We tested these compounds in vitro to draw conclusions about their cell toxicity on seven cancer cells lines and one non-neoplastic cell line. Structural requirements for antitumor activity on two different cancer cell lines were analyzed with SAR and 3D-QSAR. The 3D-QSAR models showed that steric properties could better explain the cytotoxicity of compounds than electronic properties (70% and 30% of contribution, respectively). From this analysis, we concluded that an arylpiperazinyl system connected at position 6 of the purine ring is beneficial for cytotoxic activity, while the use of bulky systems at position C-2 of the purine is not favorable. Compound 7h was found to be an effective potential agent when compared with a currently marketed drug, cisplatin, in four out of the seven cancer cell lines tested. Compound 7h showed the highest potency, unprecedented selectivity, and complied with all the Lipinski rules. Finally, it was demonstrated that 7h induced apoptosis and caused cell cycle arrest at the S-phase on HL-60 cells. Our study suggests that substitution in the purine core by arylpiperidine moiety is essential to obtain derivatives with potential anticancer activity.
Highlights
IntroductionThe generic term “cancer” refers to a large and complex group of diseases that can occur in virtually any pTahrteogf ethneerbiocdtye.rmDu“ectaonacbenr”orrmefaelrgsrotowathloarfgceellasn, tdhecsoemceplllesxprgorloifuepraotef udnicsoeansteroslltahbaltycaannd,oicncsuormine cvairsteusa, lmlyeatansytapsaizret o[1f ]t.hAe sboadcyo.nDseuqeuteonacben, tohremrealagreromwotrheotfhcaenll1s0, 0thteyspeecseollfscparnocleifre[r2a]t,eaunndcdonestrpoiltleatbhlye danivde,risnitysoamnde ccoamseps,lemxiettyasotfatshizised[1is]e
Plots of the predicted pIC50 values versus the experimental ones for the comparative molecular field analysis (CoMFA) analysis are shown in Figure 4
We found that some of these compounds were more potent than cisplatin and demonstrated unprecedented selectivity against four cancer cell lines when compared to MCR-5 cells, especially 7h
Summary
The generic term “cancer” refers to a large and complex group of diseases that can occur in virtually any pTahrteogf ethneerbiocdtye.rmDu“ectaonacbenr”orrmefaelrgsrotowathloarfgceellasn, tdhecsoemceplllesxprgorloifuepraotef udnicsoeansteroslltahbaltycaannd,oicncsuormine cvairsteusa, lmlyeatansytapsaizret o[1f ]t.hAe sboadcyo.nDseuqeuteonacben, tohremrealagreromwotrheotfhcaenll1s0, 0thteyspeecseollfscparnocleifre[r2a]t,eaunndcdonestrpoiltleatbhlye danivde,risnitysoamnde ccoamseps,lemxiettyasotfatshizised[1is]e. AAses,agecnoenrsaelqpureinncceip, ltehsegreovaerrenminogrtehtehtarnan1s0fo0rtmypateisonofocfaanncoerrm[2a]l, caenldl indtoesapmitealitghneandtivceelrlshitayveabnedencoesmtapblleixshiteyd o[3f].tThihse Idnitseeransaet,iogneanleAraglenpcryinfocirpRleessegarocvheornninCgantcheer (tIrAanRsCfo)remsatitmioanteosf tahanto1r4m.1almciellllioinntnoeawmcaalnigcenrancat sceesllohccauvrerebdeewnoersltdawbliidsheeidn [230]1. Ipt risosetsattiemcaatnecderthaartetthheerme aorset ccoumrremnotlny t3y2p.4esmfoilrliomnelniv, iwnhgecraenacsefroprawtioemntes,nd, ebsrpeaitset baenidngcodlioargencotaslecdawnciethr acarenctheretmheoslatsftrefiqvueeyneta[r4s]. Therapies aim at developing safer and more selective anticancer drugs that exhibit cytotCoxhiecmacictiavlliyty, monosmt aculirgrneannttscyenlltsh,ewticithaonutitcacanucesirndgrduagms aargeehteotehreoacltyhcylicceclolsm[5p–o8u]n. Cnuommbpeoruonfdps uI r[i2n4e] adnedrivIIat[i2v5e]s(Fhiagvuerebe2e)narseyenxtahmetpizleeds oafnddi-thaneidr tarni-tsiutubmstoitruatecdtivpiutyrinheasdbereievnatrievpesorttheadt h[2a0v–e23a]l.reCaodmy pbeoeunndtesstIed[2a4g] aainndst IcIan[2ce5r] c(eFlilgsu. These characteristics amount to an attractive pharmacological scaffold used in other anticancer pharmaceuticals [26]
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