Novel Quinoline-based Ir(III) Complexes Exhibit High Antitumor Activity in Vitro and in Vivo.

Letter CiteThis:ACSMed.Chem.Lett.2019,10,1614−1619 pubs.acs.org/acsmedchemlett Novel Quinoline-based Ir(III) Complexes Exhibit High Antitumor in Vitro in Vivo Activity and Yan Yang, †,‡,⊥ Yi-Dong Bin, †,‡,⊥ Qi-Pin Qin, *,†,∥ Xu-Jian Luo, † Bi-Qun Zou, *,§,∥ and Hua-Xin Zhang *,‡ † GuangxiKeyLabofAgriculturalResourcesChemistryandBiotechnology,CollegeofChemistryandFoodScience,YulinNormal University, 1303 Jiaoyudong Road, Yulin 537000, P. R. China ‡ School of Chemistry and Chemical Engineering, Guangxi University, 100 Daxuedong Road, Nanning 530004, P. R. China § Department of Chemistry, Guilin Normal College, 9 Feihu Road, Gulin 541001, China ∥ State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin 541004, P. R. China * S Supporting Information ABSTRACT: Eight novel Ir(III) complexes listed as [Ir(H− P) (P)]PF (PyP-Ir), [Ir(H−P) (dMP)]PF (PydMP-Ir), [Ir(H− 2 6 2 6 P) (MP)]PF (PyMP-Ir), [Ir(H−P) (tMP)]PF (PytMP-Ir), [Ir- 2 6 2 6 (MPy) (P)]PF (MPyP-Ir), [Ir(MPy) (dMP)]PF (MPydMP-Ir), 2 6 2 6 [Ir(MPy) (MP)]PF (MPyMP-Ir), [Ir(MPy) ((tMP)]PF 2 6 2 6 (MPytMP-Ir) with 2-phenylpyri-dine (H−P) and 3-methyl-2- phenylpyridine (MPy) as ancillary ligands and pyrido-[3,2-a]- pyrido[1′,2′:1,2]imidazo[4,5-c]phenazine (P), 12,13-dimethyl pyri- do-[3,2-a]-pyrido[1′,2′:1,2]-imidazo-[4,5-c]-phenazine (dMP), 2- methylpyrido [3,2-a]-pyrido-[1′,2′:1,2]-imidazo-[4,5-c]-phenazine (MP), and 2,12,13-trimethylpyrido-[3,2-a]-pyrido-[1′,2′:1,2]-imida- zo-[4,5-c]-phenazine (tMP) as main ligands, respectively, were designed and synthesized to fully characterize and explore the effect of their toxicity on cancer cells. Cytotoxic mechanism studies demonstrated that the eight Ir(III) complexes exhibited highly potent antitumor activity selectively against cancer cell lines NCI-H460, T-24, and HeLa, and no activity against HL-7702, a noncancerous cell line. Among the eight Ir(III) complexes, MPytMP-IrexhibitedthehighestcytotoxicitywithanIC =5.05±0.22nMagainstNCI-H460cells.Theantitumoractivityof 50 MPytMP-Ir in vitro could be contributed to the steric or electronic effect of the methyl groups, which induced telomerase inhibitionanddamagedmitochondriainNCI-H460cells.Moreimportantly,MPytMP-Irdisplayedasuperiorinhibitoryeffect on NCI-H460 xenograft in vivo than cisplatin. Our work demonstrates that MPytMP-Ir could potentially be developed as a novel potent Ir-based antitumor drug. KEYWORDS: Ir(III) complexes, telomerase inhibition, antitumor activity, damaging mitochondria T he capacity of tumor cells to grow, invade, and Heterocyclic compounds have been widely studied and metastasize to other organs is the driving forces in developed as potent biological compounds.23 The 5,8- cancer development.1−3 Identifying and developing new quinolinediones derived from 8-hydroxyquinoline have de- monstrable anticancer activity23 and are used as anticancer, anticancer drugs and exploring their putative antitumor antifungal,andantimalarialagents.24−28Additionally,several7- mechanismsisanurgentneed.Sincethediscoveryofcisplatin, aminoquinoline quinones, Streptonigrin, and clioquinol platinum compounds were the most successful representative derivatives,29−31 and their Ni(II),32 Yb(III),33 Sm(III),34 and drugs in clinical treatment.4 However, due to their undesired La(III)35 complexes have shown activity against senile side effects, considerable efforts have been made to develop dementia, intestinal amebiasis, and cancer.29−36 nonplatinum compounds.5,6 Recently, RuII/III, IrIII, RhIII, PdII, Inspired by the previous research and the high anticancer and AuIII, and other complexes have received significant activityofquinolinederivatives,hereweusedeasilyacquired8- attention because of their various cellular targets and hydroxylquinoline derivative 6,7- dichloro-5,8-quinolinequi- mechanisms of action.7−13 The octahedral polypyridyl Ir(III) cyclometalated complexes could induce apoptosis via regulat- Received: July25,2019 ingproteinkinasesinteractions,14−17mitochondrialmembrane Accepted: November6, 2019 disruption,18,19 or DNA binding.20−22 Published: November6, 2019 ©2019AmericanChemicalSociety 1614 DOI:10.1021/acsmedchemlett.9b00337 ACSMed.Chem.Lett.2019,10,1614−1619 .)CTU( 51:62:21 ta 0202 ,31 yluJ no RETEXE FO VINU aiv dedaolnwoD .selcitra dehsilbup erahs yletamitigel ot woh no snoitpo rof senilediuggnirahs/gro.sca.sbup//:sptth eeS ACS Medicinal Chemistry Letters Letter Chart 1. Chemical Structures of the Eight IrIII Complexes none with an AI = 1.3 ± 0.9 μM and MIC = 6.3−12.5 μg/ further study the potential interactive mechanisms of its mL37 to modify 5 a 0 nd synthesize four quinoline derivatives as biological cytotoxic influences.40−51 main ligands: pyrido-[3,2-a]-pyrido[1′,2′:1,2]imidazo[4,5-c]- FollowingthetreatmentofNCI-H460cellswithMPydMP- phenazine (P), 12,13-dimethyl pyrido-[3,2-a]-pyrido- IrandMPytMP-IratthecorrespondingIC 50 concentrationfor [1′,2′:1,2]-imidazo-[4,5-c]-phenazine (dMP), 2-methylpyrido 24 h(Figure1),apoptosisinductionwasseenin38.7% ofthe [3,2-a]-pyrido-[1′,2′:1,2]-imidazo-[4,5-c]-phenazine (MP), and 2,12,13-trimethylpyrido-[3,2-a]-pyrido-[1′,2′:1,2]-imida- zo-[4,5-c]-phenazine (tMP) (Chart S1). We studied and characterized their antineoplastic activity and explored the underlying mechanisms. Based on previously reported efficacy of [Ir(C^N) (N^N)]+,38−41 we synthesized eight novel 2 quinoline based organoiridium(III) complexes and fully characterized them (Figures S1−S48, structures shown in Chart 1). Furthermore, we also noted through HPLC Figure 1. MPydMP-Ir (125 nM) and MPytMP-Ir (5 nM) induced experiments that MPydMP-Ir and MPytMP-Ir were stable NCI-H460 cellapoptosisafter 24htreatment. for 48 h in Tris-HCl buffer (Figures S47 and S48). We studied the cytotoxic effects of the eight novel Ir(III) MPydMP-Ir treated cells, while 92.6% cells were apoptotic complexes and the free ancillary ligands against NCI-H460 following treatment with MPytMP-Ir. These results under- (nonsmall lung), T-24 (bladder), HeLa (cervical), and HL- score the greatly superior apoptosis induction capacity of 7702 (hepatocyte) using the MTT assay.42−44 The results are MPytMP-Ir. shown in Table S1. We found that the IC values of the free A 24-h treatment of NCI-H460 cells with MPydMP-Ir and 50 ancillary ligands against cancer cells were >50 μM except in MPytMP-Ir resulted in 19.75% and 49.40% inhibition of HeLa cells. In contrast, the novel Ir(III) complexes exhibited telomerase activity, respectively (Figure 2). This clearly muchsuperiorcytotoxicactivitiesagainstallthetestedhuman demonstrates that MPytMP-Ir could induce much stronger cancer cell lines except HL-7702 (noncancerous cells) telomerase inhibition than MPydMP-Ir. This provides more compared to the free ancillary ligands and cisplatin (positive evidence that increasing the methyl electron-donating groups control). Significantly, their cytotoxic activity decreased in the could enhance the telomerase inhibition via a combination of stericandelectroniceffects.45,52−58Asexpected,c-mycand/or following order: MPytMP-Ir, MPydMP-Ir, PytMP-Ir, hTERT proteins were effectively downregulated in MPydMP- PydMP-Ir, MPyMP-Ir, PyMP-Ir, MPyP-Ir, and PyP-Ir Ir and MPytMP-Ir treated cells (Figure S1) and led to against all tested cancer cells except the noncancerous HL- telomerase inhibition.52−58 7702. Furthermore, among the eight novel Ir(III) complexes, Previous studies have shown that telomerase inhibition was MPytMP-Ir exhibited significantly superior and sensitive related to cell cycle arrest in cancer cells.43,59−66 We observed cytotoxic activity with a much lower IC (5.05 ± 0.22 nM) 50 that 68.70% of the untreated NCI-H460 tumor cells were in against NCI-H460 cells. Of course, the methyl electron- the G1 phase, while this increased to 84.09% after treatment donating group does enhance the cytotoxic activity via a withMPytMP-Ir(Figure3).However,MPydMP-Irtreatment combination of steric and electronic effects, such as resultedina1.38%decreaseincellsattheG1phase.Wecould polypyridyl, pyrazine, and pyrazole ring.4,16,40,45,46 Owing to conclude that the antineoplastic activity of MPytMP-Ir wasat its highly efficient and selective cytotoxic activity against the least partly due to decreased proliferation as the cells were NCI-H460 cancer cells compared to cisplatin, we performed arrested in G1 phase.43,59−66 The expression level of CDK2, a further in-depth studies using MPytMP-Ir.16,40 We also key player in cell cycle progression, decreased slightly after compared its effectiveness to another synthesized compound treatment with MPydMP-Ir, while a slight increase in Cyclin MPydMP-Ir and used the sensitive NCI-H460 cell line to D1 was observed due to G1 arrest (Figure S2). Of note, 1615 DOI:10.1021/acsmedchemlett.9b00337 ACSMed.Chem.Lett.2019,10,1614−1619 ACS Medicinal Chemistry Letters Letter effectiveness of this compound on MMP and, in turn, on apoptosis induction.67−70 Figure 4. Degradation of MMP in MPydMP-Ir (125 nM) and MPytMP-Ir (5 nM)treatedcells. In addition, we observed that MPytMP-Ir resulted in a muchmoresignificant(FigureS2)accumulationofapaf-1and cytochrome than MPydMP-Ir. Taken together, these results demonstrate that MPytMP-Ir could cause apoptosis in NCI- H460 cells by inducing mitochondrial dysfunction.64−78 TreatmentwithMPytMP-Ir(10.0mg/kgper2days)ledto a 47.1% tumor growth inhibition on day 12.0, significantly higher than that reported for cisplatin (25.5%) (Figure 5 and Figure 2. Telomerase inhibition in NCI-H460 cells treated with MPydMP-Ir(125 nM)and MPytMP-Ir (5nM). Figure 5. Tumor volumes (A, mm3 ± SD), tumor weights (B, g ± SD),bodyweights(C,g±SD),andphotograph(D)ofNCI-H460 xenograftfollowingMPytMP-Irtreatment(n=6).**p<0.05relative to control. TablesS2−S4).71−77Moreover,MPytMP-Irtreatmentdidnot adversely affect body weight (average body weight pre- and Figure 3. NCI-H460 cell cycle analysis following MPydMP-Ir (125 post-treatment;control group,18.47 ± 1.08and 20.37± 0.52 nM)andMPytMP-Ir (5 nM)treatment. g; treated group, 18.03 ± 1.28 and 20.28 ± 0.47g). Thus, MPytMP-Ir exhibited less toxicity and better safety profile thanthatreportedforcisplatin.64,71−77Insummary,MPytMP- treatmentwithMPytMP-Irresultedinasignificantdecreasein IrdisplayedeffectiveinhibitionoftumorgrowthinNCI-H460 cyclin D1-CDK2 complex.66 These results are consistent with models. our previous expectations and investigation. In conclusion, we first synthesized eight novel quinoline- We next assessed the effect of MPytMP-Ir treatment on basedIr(III)complexesanddemonstratedtheirhighcytotoxic mitochondria using the JC-1 fluorescent mitochondrial probe. activity. Based on the first set of cytotoxicity experiments, we We saw that the green JC-1 fluorescence (damaged chose two representative complexes to further explore the mitochondria, decrease in mitochondrial membrane potential effectoftheirtoxicityinselectedcancercelllines.MPytMP-Ir [MMP]) was observed in 13.3% of NCI-H460 cells treated exhibited the most potent in vitro cytotoxicity against human with MPydMP-Ir. Strikingly, 92.2% of the cells treated with cancer cells. MPytMP-Ir also showed the highest selective MPytMP-Ir showed green fluorescence, i.e., damaged cytotoxic against NCI-H460 cancer cells and was most potent mitochondria (Figure 4). Thus, the high methyl electron- in inhibiting telomerase activity. MPytMP-Ir-induced cytotox- donating levels in MPytMP-Ir could dramatically increase the icityintheNCI-H460tumorcellswasexertedviaG1cellcycle 1616 DOI:10.1021/acsmedchemlett.9b00337 ACSMed.Chem.Lett.2019,10,1614−1619 ACS Medicinal Chemistry Letters Letter arrest, leading to inhibition of cell proliferation. Additionally, (10) Romero-Canelon, I.; Sadler, P. J. Next-generation metal MPytMP-Ir could induce cellular apoptosis by activating the anticancer complexes: multitargeting via redox modulation. Inorg. mitochondrial dysfunction pathway in the NCI-H460 tumor Chem. 2013,52, 12276−12291. cells. Last but not least, MPytMP-Ir displayed effective (11) Geldmacher, Y.; Oleszak, M.; Sheldrick, W. S. Rhodium(III) inhibition of tumor growth in NCI-H460 xenograft models and iridium(III) complexes as anticancer agents. Inorg. Chim. 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