DesignandSynthesisofNovelBicalutamideandEnzalutamide

Deriva:vesasAn:prolifera:veAgentsfortheTreatmentofProstateCancer.BasseAo,M.,Ferla,S.,Pertusa:,F.,Kandil,S.,Westwall,A.D.,Brancale,A.,McGuigan,C.,Eur.

J.Med.Chem.,2016,118,230-243

WipfgroupCurrentLit,9-10-16JamesJohnson

1

James Johnson @ Wipf Group Page 1 of 21 11/12/2016

ProstateCancerandtheAndrogenReceptor

urologygroupvirginia

•  InprostatecancerARhasahighernuclearconcentra:oninthepresenceofandrogens.

•  Commontreatmentsarethroughandrogendepriva:ontherapy:•  Surgery•  Radia:on•  Chemical

•  Androgenindependence/hypersensi:vitymuta:onsaretheresultofalowandrogenenvironment.

•  Eventuallyallpa:entsprogresstothelethalcastra:onresistantstage(CRPC).

•  CRPCisresponsibleforallprostatecancerdeathsmakingitthesecondleadingcauseofcancerdeathsinmenintheUS

•  CurrenttreatmentsofCRPConlyextendpa:entlifeby4-6months.

OH

H

H HO

H

testosteroneO

OH

H

H

H

dihydrotestosterone 2

James Johnson @ Wipf Group Page 2 of 21 11/12/2016

TheAndrogenReceptor

•  110KDaligand-induciblenuclearreceptorprotein.•  Regulatesmaledevelopmentalandphysiological

characteris:cs.•  Muta:onscanincreaseordecreasebinding

affinityofandrogensandaugmenttranscrip:onalac:vity.

•  ChangesinandrogenexpressionorARbindingaffinitydirectlyaffectthephysiologyoftheprostate

•  Currentmethodsofinhibi:oninvolvetheuseofan:androgenstoblocknucleartransloca:on/ARtranscrip:on.

PDB:3RLJ3

James Johnson @ Wipf Group Page 3 of 21 11/12/2016

CurrentFDAapproved/preclinicalTreatmentsofProstateCancer

N N

S

O

NCF3

CN

NH

O

F

ApalutamideARN-509(Phase 3)

N N

S

O

CF3

CN

NH

O

F

EnzalutamideNilutamide

BicalutamideR = H FlutamideR = OH Hydroxyflutamide Abiraterone

N

AcO

H

H HNH

O NO2

CF3 NH

CN

CF3

O

N

NO2

CF3

OHSO2

F

HN

O

O

R

TRC105(Ig)G1 anti-CD105 monoclonal antibody

(phase 2)

Ra223Alpharadin(Phase 3)

HN O

NH2F N

HN

N NDovitinib(phase 2)

OHO OR

OH

OO

OO

OHO

OBocNH

OH

R = H, DocetaxelR = Me, Carbazitaxel

J.Med.Chem.2010,53,2779–2796;EJMeCh2016,118,230-2434

James Johnson @ Wipf Group Page 4 of 21 11/12/2016

Enzalutamide/BicalutamideMOA

TherAdvUrol.2013Aug;5(4):201–210. 5

James Johnson @ Wipf Group Page 5 of 21 11/12/2016

TitlePaper

•  Improvepotency.•  Addi:onoffluorineatomsto

improvepharmacologicalandphysiochemical.

•  Decreasecytotoxic/off-targeteffects.

NH

O∗∗

Z OHX

R2

R1Y

NN

S

O

R2

R1

Fluorinated substituents

EWD substituentsFluorinated substituents

CF3, CH3Racemic/R-enantiomer

S, O, SO2

R2 = EWD substituentsPerfluoronated substituents

R1 = o-, m-, p-CF3

6

James Johnson @ Wipf Group Page 6 of 21 11/12/2016

SynthesisofbicalutamideanalogsNH

O

XArR

OH

O

Cl

NH2

R DMA, rt, 3 h

O

NH R

O

NH RO

H2O2, TFAA

CH2Cl2, rt, 24 h

NaH, ArXH

THF, rt, 24 h

X = S X = SO2mCPBA

CH2Cl2rt, 24 h

77-95% 60-86% 29-89%

40-89%

O

ClNH

CO2HNaOH

Acetone0 °C 3 h

95%

N

O

CO2H NBS

DMFrt, 3 d81%

NO

OH

O Br

24% HBr

reflux, 1 h86%

OH

O

BrHO

NH

O

XAr

HONH

O

BrHO

RSOCl2DMA

-10°C to rtovernight

80%

NH2R

NaH, ArXH

THF, rt, 24 h35-75%

X = S X = SO2mCPBA

CH2Cl2rt, 24 h45-68

SH

CF3

F3C

OBr

NaH

THF, rt, 3 h93%

S

CF3

CF3

O 1) KCN, 25% H2SO40 °C rt 20 h, 86%

2) HCl, AcOH, reflux24 h, 41%

S

CF3

F3C OH

O

OH SOCl2

DMA, rt, 72h13%

H2N CF3

NO2 CF3

NO2

S

CF3

F3C OH

O

HN

7

James Johnson @ Wipf Group Page 7 of 21 11/12/2016

Synthesisofenzalutamideanalogs

N N

S

O

NH2

R1

CSCl2, NaHCO3

CH2Cl2/H2O, rt, 24 h

NCS

R195-98%

NH2

R2

HN

R280-97%

TMSCN CN

acetone80 °C, 12h

1) DMF, rt, 48h

2) HCl, MeOH reflux, 6h

10-51%

R1R2

BrF3C

H2NO

OH

NH

F3CO

OH

K2CO3, CuCl2-acetylcyclohexanone

DMF. H2O, 105°C, 14 h NHF3C

O

OMe

NCS

R1N N

S

O

CF3

R

MeIK2CO3

DMF/H2O40 °C, 1h

DMSO/IPA84 °C, 14 h

quant. quant. 30%

8

James Johnson @ Wipf Group Page 8 of 21 11/12/2016

9

James Johnson @ Wipf Group Page 9 of 21 11/12/2016

10

James Johnson @ Wipf Group Page 10 of 21 11/12/2016

NH

O

XArR

OH

11

James Johnson @ Wipf Group Page 11 of 21 11/12/2016

12

James Johnson @ Wipf Group Page 12 of 21 11/12/2016

13

James Johnson @ Wipf Group Page 13 of 21 11/12/2016

Superposi:onbetweenthecrystalstructureoftheARintheclosedform(PDBID:1Z95)(pink)andthenewopenARmodel(lightblue).14

James Johnson @ Wipf Group Page 14 of 21 11/12/2016

Dockingof(R)-bicalutamide(carbonatomsinpink)intheARhomologymodel(lightblue) 15

James Johnson @ Wipf Group Page 15 of 21 11/12/2016

16

James Johnson @ Wipf Group Page 16 of 21 11/12/2016

17

James Johnson @ Wipf Group Page 17 of 21 11/12/2016

18

James Johnson @ Wipf Group Page 18 of 21 11/12/2016

19

James Johnson @ Wipf Group Page 19 of 21 11/12/2016

MTTassay

Caco-2cellpermeabilitytest

20

James Johnson @ Wipf Group Page 20 of 21 11/12/2016

Conclusions

•  SynthesizedseveralnewantagonistsofAR•  Newanalogsshowincreasedpotencytoenzalutamideresistantcelllines.

•  Compoundss:llshowcytotoxicity.•  PreparedahomologymodelofARtopredictfuturestructuralmodifica:ons.

•  PossiblenewmechanismofantagonismofAR

21

James Johnson @ Wipf Group Page 21 of 21 11/12/2016