(R)-Bicalutamide is the R-enantiomer of Bicalutamide. (R)-Bicalutamide is an androgen receptor (AR) antagonist (inhibitor) with anticancer effect. (R)-Bicalutamide is extensively used in prostate cancer research.

Physicochemical Properties

Molecular Formula	C18H14F4N2O4S
Molecular Weight	430.37
Exact Mass	430.061
Elemental Analysis	C, 50.23; H, 3.28; F, 17.66; N, 6.51; O, 14.87; S, 7.45
CAS #	113299-40-4
Related CAS #	Bicalutamide;90357-06-5
PubChem CID	56069
Appearance	White to off-white solid powder
Density	1.5±0.1 g/cm3
Boiling Point	650.3±55.0 °C at 760 mmHg
Melting Point	178-181ºC
Flash Point	347.1±31.5 °C
Vapour Pressure	0.0±2.0 mmHg at 25°C
Index of Refraction	1.578
LogP	4.94
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	9
Rotatable Bond Count	5
Heavy Atom Count	29
Complexity	750
Defined Atom Stereocenter Count	1
SMILES	C[C@](CS(=O)(=O)C1=CC=C(C=C1)F)(C(=O)NC2=CC(=C(C=C2)C#N)C(F)(F)F)O
InChi Key	LKJPYSCBVHEWIU-KRWDZBQOSA-N
InChi Code	InChI=1S/C18H14F4N2O4S/c1-17(26,10-29(27,28)14-6-3-12(19)4-7-14)16(25)24-13-5-2-11(9-23)15(8-13)18(20,21)22/h2-8,26H,10H2,1H3,(H,24,25)/t17-/m0/s1
Chemical Name	(2R)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluorophenyl)sulfonyl-2-hydroxy-2-methylpropanamide
Synonyms	(R)-Bicalutamide; 113299-40-4; (R)-Casodex; (-)-Bicalutamide; R-BICALUTAMIDE; (2R)-N-[4-CYANO-3-(TRIFLUOROMETHYL)PHENYL]-3-[(4-FLUOROPHENYL)SULFONYL]-2-HYDROXY-2-METHYLPROPANAMIDE; Bicalutamide, (R)-; Bicalutamide, (-)-;
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	AR/androgen receptor[1]
ln Vitro	Racemic mixtures containing becalutamide are accessible. Approximately thirty times more binding affinity of R isomer (R-bicalutamide) to AR exists than that of S isomer [1]. In a dose-dependent manner, (R)-bicalutamide (0.02 – 20 μM) decreases the survival of naive LNCaP cells [2]. Bicalutamide is a first generation antiandrogen used to treat prostate cancer, which was approved for clinical application in 1995. Bicalutamide is available as a racemic mixture. However the R isomer (R-bicalutamide Fig. 1) has an ≈30-fold higher binding affinity to the AR than the S isomer and was therefore used in this study. Although R-bicalutamide treatment has a good effect initially, prostate tumors will lose their sensitivity to the antiandrogen and become refractory after 2–3 years. The underlying mechanism is not clear, but mutation of the AR has frequently been reported. Some hot–spot mutations have been linked to treatment with individual anti-androgens, such as T877A, with hydroxyflutamide (HF) treatment, and W741(C/L), with bicalutamide treatment.[1] In order to investigate the effect of different mutations of AR on the efficacy of R-bicalutamide, MD simulations, MM-GBSA binding free energy calculations and per-residue decomposition methods were performed to analyze the interaction mechanism of R-bicalutamide with WT/mutant ARs. MD simulations show that helix H12 plays a vital role for the binding between R-bicalutamide and ARs. When the B-ring of R-bicalutamide is close to helix H12, H12 will be pushed aside, which distorts the coactivator binding site and results in the inactivation of transcription. So we in silico verified that the mutations of T877A, F876L, F876L_T877A and L701H could not switch R-bicalutamide from an AR antagonist to agonist. In addition, when the B-ring of R-bicalutamide is far away from helix H12, steric clash is reduced, which is favorable for H12 closing, resulting in effective coactivator binding site formation and promoting transcription. Our data indicate that the single mutation of W741C and double mutations of W741C_T877A can switch R-bicalutamide from AR antagonist to agonist. Furthermore, the per-residue free energy decomposition shows that, once the contribution of residue M895 increases, M895, together with H12, becomes stable, which is conductive to the formation of effective coactivator binding site to facilitate transcription.[1]
ln Vivo	In VCaP xenograft mice, (R)-Bicalutamide (10 mg/kg; ig; daily; for 4 days) exhibits antitumor efficaciousness[3].
Enzyme Assay	In order to investigate the effect of different mutations of AR on the efficacy of R-bicalutamide, MD simulations, MM-GBSA binding free energy calculations and per-residue decomposition methods were performed to analyze the interaction mechanism of R-bicalutamide with WT/mutant ARs. MD simulations show that helix H12 plays a vital role for the binding between R-bicalutamide and ARs. When the B-ring of R-bicalutamide is close to helix H12, H12 will be pushed aside, which distorts the coactivator binding site and results in the inactivation of transcription. So we in silico verified that the mutations of T877A, F876L, F876L_T877A and L701H could not switch R-bicalutamide from an AR antagonist to agonist. In addition, when the B-ring of R-bicalutamide is far away from helix H12, steric clash is reduced, which is favorable for H12 closing, resulting in effective coactivator binding site formation and promoting transcription. Our data indicate that the single mutation of W741C and double mutations of W741C_T877A can switch R-bicalutamide from AR antagonist to agonist. Furthermore, the per-residue free energy decomposition shows that, once the contribution of residue M895 increases, M895, together with H12, becomes stable, which is conductive to the formation of effective coactivator binding site to facilitate transcription.[1]
Cell Assay	Establishment of LNCaP-Rbic subclone[2] LNCaP cells were continuously exposed to 20 μM of (R)-bicalutamide for 8 months and after only a few days LNCaP cell proliferation was strongly hampered. Such conditions persisted for the entire 8-month period, after which cells started to proliferate again and in only a few weeks a subclone of actively proliferating cells was isolated, established and called LNCaP-Rbic. This clone exhibited a faster growth than that of the parental cell line and a substantially reduced doubling time from 55 to 37...[2]
Animal Protocol	Animal/Disease Models: CD1 male nude (nu/nu) mice, with VCaP xenografts[3] Doses: 10 mg/kg Route of Administration: Orally gavage, daily, for 4 consecutive weeks Experimental Results: Suppressed tumor growth.
References	[1]. Molecular mechanism of R-bicalutamide switching from androgen receptor antagonist to agonist induced by amino acid mutations using molecular dynamics simulations and free energy calculation. J Comput Aided Mol Des. 2016 Dec;30(12):1189-1200. [2]. Prolonged exposure to (R)-bicalutamide generates a LNCaP subclone with alteration of mitochondrial genome. Mol Cell Endocrinol. 2014 Jan 25;382(1):314-324. [3]. Effect of Small Molecules Modulating Androgen Receptor (SARMs) in Human Prostate Cancer Models. PLoS One. 2013; 8(5): e62657.
Additional Infomation	(R)-bicalutamide is a N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide that is the (R)-enantiomer of bicalutamide. It has a role as an androgen antagonist and an antineoplastic agent. It is an enantiomer of a (S)-bicalutamide. See also: Bicalutamide (annotation moved to).

Solubility Data

Solubility (In Vitro)

DMSO: 100 mg/mL (232.36 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.81 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.81 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (5.81 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.3236 mL	11.6179 mL	23.2358 mL
	5 mM	0.4647 mL	2.3236 mL	4.6472 mL
	10 mM	0.2324 mL	1.1618 mL	2.3236 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.