Small Molecule Antagonists of the Nuclear Androgen Receptor for the Treatment of Castration-Resistant Prostate Cancer

Abstract

After a high-throughput screening campaign identified thioether 1 as an antagonist of the nuclear androgen receptor, a zone model was developed for structure–activity relationship (SAR) purposes and analogues were synthesized and evaluated in a cell-based luciferase assay. A novel thioether isostere, cyclopropane (1S,2R)-27, showed the desired increased potency and structural properties (stereospecific SAR response, absence of a readily oxidized sulfur atom, low molecular weight, reduced number of flexible bonds and polar surface area, and drug-likeness score) in the prostate-specific antigen luciferase assay in C4-2-PSA-rl cells to qualify as a new lead structure for prostate cancer drug development.

Co(II)‐salen catalyzed stereoselective cyclopropanation of fluorinated styrenes

“…We expected catalyst 8 to be sufficiently reactive to provide the desired product stereoselectivity even with a fluorinated styrene . To test this hypothesis, we selected the more potent enantiomer of our lead compound, ( − ) ‐JJ‐450 , as the target compound (Scheme ).…”

“…The crude residue was purified by chromatography on SiO 2 (1:1, hexanes: EtOAc) to afford ( − ) ‐JJ‐450 ( 13 , 0.130 g, 0.349 mmol, 91%) as a viscous oil: [α] 20 D −159.4 ( c 1.67, CHCl 3 ); IR (CH 2 C l2 ) 2916, 2819, 1638, 1593, 1512, 1489, 1465, 1436, 1224, 1098, 1034, 941, 838, 815, 732 cm −1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.16‐7.10 (m, 2H), 7.06 (d, J = 8.1 Hz, 1H), 7.01‐6.92 (m, 3H), 6.72 (d, J = 2.0 Hz, 1H), 3.86‐3.74 (m, 1H), 3.74‐3.57 (m, 2H), 3.40‐3.28 (m, 1H), 2.82‐2.66 (m, 2H), 2.44 (q, J = 8.9 Hz, 1H), 2.35‐2.26 (m, 1H), 2.26‐2.14 (m, 5H), 1.82 (q, J = 5.8 Hz, 1H), 1.34 (td, J = 8.4, 5.5 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 167.3, 161.7 (d, J = 244.9 Hz), 151.9, 133.2 (d, J = 3.1 Hz), 132.0 (d, J = 19.9 Hz), 131.0, 129.2 (d, J = 7.9 Hz), 123.7, 119.8, 115.1 (d, J = 21.3 Hz), 51.9, 51.7, 45.6, 42.3, 23.9, 23.6, 17.4, 10.8; 19 F NMR (376 MHz, CDCl 3 ) δ −116.3; HRMS (ESI+) m / z calcd for C 21 H 23 ON 2 ClF [M + H] 373.1478, found 373.1488. The enantiomeric ratio was determined as 97:3 er by HPLC (Chiralpak AD‐H, hexane:isopropanol (9:1), 23°C, 254 nm, flow rate: 1 mL/min; major isomer Rt 12.6 min; minor isomer Rt 15.3 min) …”

“…Cyclopropanes are also successfully used as bioisosteres for alkenes in pharmaceuticals, polyene natural products, and in peptide mimetics . In 2016, we disclosed the structure of a cis ‐cyclopropyl carboxamide, JJ‐450 , developed through an extensive structure‐activity relationship (SAR) study, with single digit micromolar activity in a castration‐resistant prostate cancer (CRPC) model . Significantly, the two enantiomers of the cis ‐cyclopropane lead structure showed a 10‐fold difference in activity, and the trans ‐cyclopropane was much less active (Figure ) .…”

“… Cis ‐cyclopropanes ( − ) ‐JJ‐450 and ( + ) ‐JJ‐450 showed IC 50 = 1.7μM and 15.2μM, respectively, in a luciferase reporter assay for the translocation of androgen receptor…”

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

“…Putative binding modes of compound 57 [ Figure 15], the most active of the series (IC 50 = 0.93 in 22Rv1 cells), within the antagonistic AR-LBD showed hydrogen bond interactions with key amino acids Arg752, Gln711 (with the lactone carbonyl group), Thr877 (with the terminal carbonyl group) and Asn705 (with the methylene group). Another interesting example of an innovative structureis represented by the molecule synthesised by Johnson et al [129] (compound 58), though only the PSA luciferase assay was conducted to evaluate biological activity. BMS-641988 (59) is a non-steroidal compound disclosed in 2015 with high binding affinity for the AR (K i = 1.7 nmol/L), efficacious in a CWR22-BMSLD1 PCa xenograft model with superior efficacy to bicalutamide.…”