New steroidal 17β-carboxy derivatives present anti-5α-reductase activity and anti-proliferative effects in a human androgen-responsive prostate cancer cell line.
The androgens testosterone (T) and dihydrotestosterone (DHT), besides playing an important role in prostate development and growth, are also responsible for the development and progression of benign prostate hyperplasia (BPH) and prostate cancer. Therefore, the actions of these hormones can be antagonized by preventing the irreversible conversion of T into DHT by inhibiting 5α-reductase (5α-R). This has been a useful therapeutic approach for the referred diseases and can be achieved by using 5α-reductase inhibitors (RIs). Steroidal RIs, finasteride and dutasteride, are used in clinic for BPH treatment and were also proposed for chemoprevention of prostate cancer. Nevertheless, due to the increase in bone and muscle loss, impotency and occurrence of high-grade prostate tumours, it is important to seek for other potent and specific molecules with lower side effects. In the present work, we designed and synthesized steroids with the 3-keto-Δ(4) moiety in the A-ring, as in the 5α-R substrate T, and with carboxamide, carboxyester or carboxylic acid functions at the C-17β position. The inhibitory 5α-R activity, in human prostate microsomes, as well as the anti-proliferative effects of the most potent compounds, in a human androgen-responsive prostate cancer cell line (LNCaP cells), were investigated. Our results showed that steroids 3, 4 and 5 are good RIs, which suggest that C-17β lipophylic amides favour 5α-R inhibition. Moreover, these steroids induce a decrease in cell viability of stimulated LNCaP cells, in a 5α-R dependent-manner, similarly to finasteride.
Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, n° 228, 4050-313 Porto, Portugal; Institute for Molecular and Cell Biology (IBMC), University of Porto, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal.
Cristina
C
Amaral
Carla
C
Varela
Georgina
G
Correia-da-Silva
Elisiário
E
Tavares da Silva
Rui A
RA
Carvalho
Saul C P
SC
Costa
Sara C
SC
Cunha
José O
JO
Fernandes
Natércia
N
Teixeira
Fernanda M F
FM
Roleira
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D042944:Cholestenone 5 alpha-Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013196:Dihydrotestosterone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D013739:Testosterone / Q000378:metabolism
D004791:Enzyme Inhibitors; D013196:Dihydrotestosterone; D013739:Testosterone; D042944:Cholestenone 5 alpha-Reductase
(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; 1,4-dithioerythritol; 5α-R; 5α-reductase; 5α-reductase inhibitors; AR; ATCC; American Type Culture Collection; BOP; BPH; BSA; Benign prostate hyperplasia; CFBS; DHT; DHT-(13)C(3); DLLME; DMSO; DTE; DTT; F; FBS; FDA; Finasteride; Food and Drug Administration; GC–MS; LDH; LNCaP cells; MSTFA; MTT; MeCN; MeOH; N-methyl-N-(trimethylsilyl)trifluoroacetamide; NADPH; Prostate cancer; RIs; RPMI; RT; Roswell Park Memorial Institute; SEM; Steroidal 5α-reductase inhibitors; T; T-d(3); acetonitrile; androgen receptor; benign prostate hyperplasia; bovine serum albumin; dihydrotestosterone; dihydrotestosterone (13)C(3) solution; dimethyl sulfoxide; dispersive liquid–liquid microextraction; dithiothreitol; fetal bovine serum; finasteride; gas chromatography–mass spectrometry; human androgen-responsive prostate cancer cell line; lactate dehydrogenase; methanol; nicotinamide adenine dinucleotide phosphate; pre-treated charcoal heat-inactivated fetal bovine serum; room temperature; standard error of mean; testosterone; testosterone-d(3) solution; tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-difenyltetrazolium