Design and Synthesis of Novel Bicalutamide and Enzalutamide Deriva:ves as An:prolifera:ve Agents for the Treatment of Prostate Cancer.
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1 Design and Synthesis of ovel Bicalutamide and Enzalutamide Deriva:ves as An:prolifera:ve Agents for the Treatment of Prostate Cancer. BasseAo, M., Ferla, S., Pertusa:, F., Kandil, S., Westwall, A. D., Brancale, A., McGuigan, C., Eur. J. Med. Chem., 2016, 118, Wipf group Current Lit, James Johnson 1 James Wipf Group Page 1 of 21 11/12/2016
2 Prostate Cancer and the Androgen Receptor In prostate cancer AR has a higher nuclear concentra:on in the presence of androgens. Common treatments are through androgen depriva:on therapy: Surgery Radia:on Chemical Androgen independence/hypersensi:vity muta:ons are the result of a low androgen environment. Eventually all pa:ents progress to the lethal castra:on resistant stage (CRPC). CRPC is responsible for all prostate cancer deaths making it the second leading cause of cancer deaths in men in the US Current treatments of CRPC only extend pa:ent life by 4-6 months. urologygroupvirginia testosterone dihydrotestosterone 2 James Wipf Group Page 2 of 21 11/12/2016
3 The Androgen Receptor 110 KDa ligand-inducible nuclear receptor protein. Regulates male developmental and physiological characteris:cs. Muta:ons can increase or decrease binding affinity of androgens and augment transcrip:onal ac:vity. Changes in androgen expression or AR binding affinity directly affect the physiology of the prostate Current methods of inhibi:on involve the use of an:androgens to block nuclear transloca:on/ar transcrip:on. PDB: 3RLJ 3 James Wipf Group Page 3 of 21 11/12/2016
4 Current FDA approved/preclinical Treatments of Prostate Cancer R 2 R = Flutamide R = ydroxyflutamide F S 2 Bicalutamide C Ac Abiraterone ilutamide 2 F S Enzalutamide C F S Apalutamide AR-509 (Phase 3) C R Boc R =, Docetaxel R = Me, Carbazitaxel F 2 Dovitinib (phase 2) J. Med. Chem. 2010, 53, ; EJMeCh 2016, 118, TRC105 (Ig)G1 anti-cd105 monoclonal antibody (phase 2) Ra 223 Alpharadin (Phase 3) 4 James Wipf Group Page 4 of 21 11/12/2016
5 Enzalutamide/Bicalutamide MA Ther Adv Urol Aug; 5(4): James Wipf Group Page 5 of 21 11/12/2016
6 Title Paper Improve potency. Addi:on of fluorine atoms to improve pharmacological and physiochemical. Decrease cytotoxic/off-target effects. Fluorinated substituents R 2 S,, S 2 X Z, C 3 Racemic/R-enantiomer R 1 Y EWD substituents Fluorinated substituents R 2 = EWD substituents Perfluoronated substituents S R 1 R 2 R 1 = o-, m-, p- 6 James Wipf Group Page 6 of 21 11/12/2016
7 Synthesis of bicalutamide analogs Cl 2 R 2 2, TFAA a, ArX DMA, rt, 3 h R C 2 Cl 2, rt, 24 h R TF, rt, 24 h 77-95% 60-86% 29-89% Ar X R X = S mcpba C 2 Cl 2 rt, 24 h X = S % Cl C 2 a Acetone 0 C 3 h 95% C 2 BS DMF rt, 3 d 81% Br 24% Br reflux, 1 h 86% Br R SCl 2 DMA -10 C to rt overnight 80% 2 Br R a, ArX TF, rt, 24 h 35-75% Ar X X = S mcpba C 2 Cl 2 rt, 24 h X = S 2 S F 3 C a TF, rt, 3 h 93% Br S 1) KC, 25% 2 S 4 0 C rt 20 h, 86% 2) Cl, Ac, reflux 24 h, 41% 2 F 3 C F 2 3 C S SCl 2 S DMA, rt, 72h 13% 2 7 James Wipf Group Page 7 of 21 11/12/2016
8 Synthesis of enzalutamide analogs 2 CSCl 2, ac 3 CS R 1 C 2 Cl 2 / 2, rt, 24 h 95-98% R 1 1) DMF, rt, 48h R 1 S R 2 2 TMSC C 2) Cl, Me reflux, 6h 10-51% R 2 acetone 80 C, 12h 80-97% R 2 2 CS F 3 C Br K 2 C 3, CuCl 2-acetylcyclohexanone DMF. 2, 105 C, 14 h quant. F 3 C MeI K R 2 C 3 1 Me DMF/ 2 F 3 C DMS/IPA 40 C, 1h 84 C, 14 h quant. 30% S R 8 James Wipf Group Page 8 of 21 11/12/2016
9 James Wipf Group Page 9 of 21 11/12/2016 9
10 James Wipf Group Page 10 of 21 11/12/
11 Ar X R 11 James Wipf Group Page 11 of 21 11/12/2016
12 James Wipf Group Page 12 of 21 11/12/
13 James Wipf Group Page 13 of 21 11/12/
14 14 Superposi:on between the crystal structure of the AR in the closed form (PDB ID: 1Z95) (pink) and the new open AR model (light blue). James Wipf Group Page 14 of 21 11/12/2016
15 Docking of (R)-bicalutamide (carbon atoms in pink) in the AR homology model (light blue) James Wipf Group Page 15 of /12/2016
16 16 James Wipf Group Page 16 of 21 11/12/2016
17 James Wipf Group Page 17 of 21 11/12/
18 James Wipf Group Page 18 of 21 11/12/
19 James Wipf Group Page 19 of 21 11/12/
20 Caco-2 cell permeability test MTT assay 20 James Wipf Group Page 20 of 21 11/12/2016
21 Conclusions Synthesized several new antagonists of AR ew analogs show increased potency to enzalutamide resistant cell lines. Compounds s:ll show cytotoxicity. Prepared a homology model of AR to predict future structural modifica:ons. Possible new mechanism of antagonism of AR 21 James Wipf Group Page 21 of 21 11/12/2016
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