Purpose One of the most disturbing tendencies lately is the development Purpose One of the most disturbing tendencies lately is the development

Supplementary Materialsml4001744_si_001. triggered by binding of endogenous androgens, such as for example testosterone and its own activated type, dihydrotestosterone (DHT), and regulates several physiological procedures, including development, maintenance of the man reproductive system, and homeostasis of muscle tissue and bone tissue.3,4 Because AR takes on an important role in progression of prostate cancer, AR antagonists are used clinically for treatment of prostate cancer. However, chronic administration of AR antagonists often leads to development of resistance, so-called castration-resistant prostate cancer (CRPC),5,6 and mutation of AR is thought to be the main cause.7?9 For example, a representative nonsteroidal AR antagonist, flutamide (1), and its activated metabolite, hydroxylflutamide (2), act as agonists of AR bearing T877A, the most common mutation of AR in CRPC and consequently exacerbate the cancer.10 All the nonsteroidal AR antagonists currently Everolimus small molecule kinase inhibitor in clinical use are derivatives of flutamide bearing a nitrophenyl or a cyanophenyl group as the pharmacophore (Figure ?(Figure11),11 and these antagonists are often ineffective for mutated ARs.12 Intensive studies based on flutamide derivatives have been investigated, and recently, novel flutamide derivative MDV3100 Rabbit Polyclonal to B3GALTL (5) was developed as a Everolimus small molecule kinase inhibitor potent AR antagonist effective for CRPC.13 Another possible approach to overcome CRPC would be to develop AR antagonists bearing a novel pharmacophore, different from those of flutamide analogues. For example, nicotinamide derivative DIMN (6) was developed as novel type of nonsteroidal AR antagonists.14 Open in a separate window Figure 1 Structures of nonsteroidal AR antagonists. With the aim of developing novel AR antagonists, we focused on the structure of the natural pigment curcumin (7, Figure ?Figure2).2). Several curcumin analogues possess antiandrogenic activity,15,16 and 7 does not possess the cyanophenyl or nitrophenyl group that is the key structure of potent nonsteroidal AR antagonists so far created. Structurally, curcumin (7) includes two phenolic organizations connected by an unsaturated 1,3-diketone (or its enol type), which will be and metabolically reactive chemically.17 Therefore, we assumed that at least one phenolic band of 7 was needed for the AR antagonistic activity which the entire structural platform of 7 could possibly be replaced by steady, drug-like constructions. Our previous research on retinoids recommended that benzanilide can be a versatile framework for changing conjugated polyene substructure.18,19 Recent tests by us yet others recommended a PhCXCPh skeleton also, such as for example diphenylmethane (X = carbon),20 diphenyl ether (X = oxygen),21 diphenylamine (X = nitrogen),22 or diphenylsilane (X = silane),23 is the right hydrophobic substructure for nuclear receptor ligands. Open up in another window Shape 2 Style of book AR antagonists bearing phenol substructure. Based on those results, we designed the phenoxybenzanilide primary framework as an applicant scaffold of AR antagonists, and we primarily synthesized the mother or father substance 8 (Shape ?(Figure2).2). Biological evaluation exposed that 8 exhibited significant AR antagonistic activity, being truly a potent inhibitor of androgen-dependent SC-3 cell24 proliferation (IC50 = 9.4 M). Here, we report the synthesis and biological activity of 8 and its derivatives (general formula shown in Figure ?Figure2)2) as candidate new-generation AR antagonists bearing a novel pharmacophore distinct from those of conventional flutamide analogues. Compound 8 and 4-phenoxyphenols 12aCp were synthesized as shown in Scheme 1.25 SNAr reaction using 4-fluoronitrobenzene (9) and hydroquinone gave diphenyl ether 10, and then reduction of the nitro group afforded primary amine 11. Amide bond formation of 11 with benzoic acid or benzoyl chloride derivatives gave compounds 8 and 12aCp. Compounds 12c, 12f, and 12h were synthesized from the corresponding em O /em -monomethyl (for 12c) or em O /em -monoacetyl (for 12f and 12h) derivatives by removal of the em O /em -substituent. Diphenyl ether 15 without a phenolic hydroxyl group Everolimus small molecule kinase inhibitor was also prepared for investigation of the significance of the phenolic hydroxyl group. SNAr reaction using 7 and phenol gave diphenyl ether 13, and then reduction of the nitro group afforded primary amine 14. Amide bond formation of 14 using benzoyl chloride gave compound 15 (Scheme 1). Open in a separate window Scheme 1 Synthesis of 8, 12aCp, and 15Reagents and conditions: (a) hydroquinone, NaOH, DMSOCH2O, 50 C, 56%; (b) PdCC, H2, MeOH, rt, 92C98%; (c) method A, aroyl chloride, THF, rt, 55C86%; method B, aroyl chloride, pyridine, rt, 50C60%; method C, (i) (COCl)2, DMF, CH2Cl2, rt; (ii) 11, THF, rt, 39C84%; method D, (i) (COCl)2, DMF, CH2Cl2, rt; (ii) 11, pyridine, THF, rt, 46%; (d) BBr3, CH2Cl2, 40 C, 50%; (e) K2CO3, MeOHCH2O, rt, 95%; (f) NaOEt, EtOH, rt, 30%; (g) phenol, K2CO3, DMF, 40 C, 90%. Scheme 2 shows the synthesis of compounds 22 and 23 bearing methyl group(s) at the central benzene ring and the synthesis of heterocyclic.

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