title: Stereocontrolled synthesis of the four 16-hydroxymethyl-19-nortestosterone isomers and their antiproliferative activities.
abstract: Novel 16-hydroxymethyl-19-nortestosterone diastereomers were prepared by Birch reduction from the corresponding 3-methoxy-16-hydroxymethylestra-1,3,5(10)-trien-17-ol isomers with known configurations. The synthesized compounds are 16α- and 16β-hydroxymethyl-substituted 19-nortestosterone and their 17α-epimers. To prepare 17α-19-nortestosterone, the Mitsunobu inversion reaction of 19-nortestosterone with different alkyl and aryl carboxylic acids was chosen. Deacylation of the new compounds by the Zemplén method yielded the required 17α-19-nortestosterone. The antiproliferative activities of the structurally related compounds were determined in vitro through microculture tetrazolium assays on a panel of human adherent cervical (HeLa, SiHa and C33A), breast (MCF-7, MDA-MB-231, MDA-MB-361 and T47D) and ovarian (A2780) cell lines. The 17α epimer of 19-nortestosterone demonstrated considerable activity, selectively for HeLa cells, with a calculated IC50 of 0.65 μM. The reference compound, cisplatin, displayed an order of magnitude higher IC50 (12.4 μM). The cancer selectivity of 17α-19-nortestosterone was tested by MTT assay performed with noncancerous human fibroblast cell line MRC-5. The results indicated that 17α-19-nortestosterone selectively disturbs the viability of HeLa cells without greatly affecting other cancer cell types and intact fibroblasts.
authors.affiliation: Department of Organic Chemistry, University of Szeged, Dóm tér 8., H-6720 Szeged, Hungary. Electronic address: schneider@chem.u-szeged.hu.
authors.forename: Gyula
authors.initials: G
authors.lastname: Schneider
authors.affiliation: Department of Organic Chemistry, University of Szeged, Dóm tér 8., H-6720 Szeged, Hungary.
authors.forename: Anita
authors.initials: A
authors.lastname: Kiss
authors.affiliation: Department of Organic Chemistry, University of Szeged, Dóm tér 8., H-6720 Szeged, Hungary.
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Mernyák
authors.affiliation: Department of Organic Chemistry, University of Szeged, Dóm tér 8., H-6720 Szeged, Hungary.
authors.forename: Zsanett
authors.initials: Z
authors.lastname: Benke
authors.affiliation: Department of Organic Chemistry, University of Szeged, Dóm tér 8., H-6720 Szeged, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Wölfling
authors.affiliation: Department of Organic Chemistry, University of Szeged, Dóm tér 8., H-6720 Szeged, Hungary.
authors.forename: Éva
authors.initials: É
authors.lastname: Frank
authors.affiliation: Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6., H-6720 Szeged, Hungary.
authors.forename: Noémi
authors.initials: N
authors.lastname: Bózsity
authors.affiliation: Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6., H-6720 Szeged, Hungary.
authors.forename: András
authors.initials: A
authors.lastname: Gyovai
authors.affiliation: Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6., H-6720 Szeged, Hungary.
authors.forename: Renáta
authors.initials: R
authors.lastname: Minorics
authors.affiliation: Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6., H-6720 Szeged, Hungary. Electronic address: zupko@pharm.u-szeged.hu.
authors.forename: István
authors.initials: I
authors.lastname: Zupkó
mesh_terms: D045930:Anabolic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000728:Androgens / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D009277:Nandrolone / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: D045930:Anabolic Agents; D000728:Androgens; D009277:Nandrolone; D002945:Cisplatin
keywords: 17α-19-Nortestosterone; 19-Nortestosterone; Antiproliferative activity; Birch reduction; Stereocontrolled synthesis