Abstract
An expansion of the structure–activity relationship study of CXCR4 antagonists led to the synthesis of a series of isoquinolines, bearing a tetrahydroquinoline or a 3-methylpyridinyl moiety as head group. All compounds were investigated for CXCR4 affinity and antagonism in competition binding and calcium mobilization assays, respectively. In addition, the anti-HIV activity of all analogues was determined. All compounds showed excellent activity, with compound 24c being the most promising one, since it displayed consistently low nanomolar activity in the various assays.
Highlights
The CXC chemokine receptor 4 (CXCR4) is a seven transmembrane G protein-coupled receptor (GPCR), whose only endogenous ligand is the CXC chemokine ligand 12 (CXCL12), known as stromal cell-derived factor 1 (SDF-1)
An expansion of the structure–activity relationship study of CXCR4 antagonists led to the synthesis of a series of isoquinolines, bearing a tetrahydroquinoline or a 3-methylpyridinyl moiety as head group
CXCR4 is the main coreceptor of human immunodeficiency virus (HIV)-1 in the later stages of infection, that leads to a decrease in CD4 cell count and is linked to a higher chance of advancing to the acquired immune deficiency syndrome (AIDS) [2]
Summary
The CXC chemokine receptor 4 (CXCR4) is a seven transmembrane G protein-coupled receptor (GPCR), whose only endogenous ligand is the CXC chemokine ligand 12 (CXCL12), known as stromal cell-derived factor 1 (SDF-1). AMD3100 (Plerixafor, compound 1, Figure 1) received marketing approval for hematopoietic stem cell mobilization for transplantations in case of non-Hodgltkiyocimoanllplttyohomoodlmpethoamodaomnenmdastaomrnnaudstelttmritaphutleaeltttimhpsamlyeteasmlmollymamelalloo[mml8e]oca.ulIe[nl8ce]ua.aldIenndtaaiantdgitodoangnit,oiiAsonmniMs,mAoDfM3oC1fD0XC03CX1hRC0a04sRhb4isaeisseanbapeupreosrneomdumissaieissdninagagcsshstaetrrcamahtteieecgmgaylyffoorr tthhee ttrreeaattmmeenntt ooff ddiiffffeerreennttccaanncceerrss,, ssuucchh aassbbrreeaassttccaanncceerr[[99]],,pprroossttaatteeccaanncceerr[[1100]], ,aanndd oovvaarriiaann ccaanncceerr [[1111]]. IInn22001166,,oouurrggrorouupprerpeporotretdeda ammeteatla-flr-efreetehtrheere-ceo-cmopmopnoenet nretarcetaioctniofnorftohrethsyenstyhnetshiseosifs 1o,5f -1d,i5s-udbisutibtustietdut1e,d2,31-,t2r,i3a-ztorilaezso[l2e0s–2[220],–k22n]o,wknoaws ntheas“ttrhiaez“otlriziaaztoiolinzaretiaocntiorneaocftikoentoonfeks”e.Itnon2e0s2”0.,Init 2w0a2s0,siht owwans sbhyowounr blayboourartloarbyortahtaotrythtehaatcitdh-emaecdidia-mteedddiaetneditrdoegneintraotigveenaritnivge opening of triazoloisoquinolines furnished various 1-methyleneisoquinolines [23] In this manuscript, these synthetic methodologies were applied for the synthesis of a series of novel isoquinoline-based CXCR4 antagonists, derived from the lead compound 4. Ring opening of triazoloisoquinolines furnished various 1-methyleneisoquinolines [23] A reductive amination between amine 18 and the commercially available picolinaldehyde in presence of NaBH(OAc), followed by Boc deprotection, furnished the final compound 20 [14,27]. RReeaaggeenntstsananddcocnodnidtiotinosn:sa:) (naB)unLBiu(L1.i6(M1.6inMheinxahneex),aDneM),FD, EMt2FO, ,E2t42Oh,(6224%hy(i6e2ld%);ybi)el1d7),;N(ba)BH17(,ONAacB)3H, D(OCAE,c)r3t, D48ChE,(7rt4,%48yhiel(d7)4;%c):y(iie)ld15);a(–cd):, K(i2)C1O5a3,–Md,eKC2NC,Or3e,flMuxe,C2Nd, (r5e7fl–u8x4,%2 ydie(l5d7)–; 8(4ii%) TyFiAel,dD);C(iMi),TrFt,A1, hDC(9M9%, ryt,ie1ldh);(d99):%(i)yipeilcdo)-; (ldin):a(ldi)ephiycodlei,nNaladBeHhy(OdeA, cN)3a,BDHC(EO,Artc,)23,dD(C52E%, rty,i2eldd)(;5(2ii%) TyFieAld, )D; C(iiM) T, rFtA, 1, DhC(8M1%, rty, i1elhd)(8. 1% yield)
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