title: Synthesis and molecular modeling of novel tetrahydro-β-carboline derivatives with phosphodiesterase 5 inhibitory and anticancer properties.
abstract: New derivatives based upon the tetrahydro-β-carboline-hydantoin and tetrahydro-β-carboline-piperazinedione scaffolds were synthesized. All compounds were evaluated for their ability to inhibit PDE5 in vitro, and numerous compounds with IC(50) values in the low nanomolar range were identified including compounds derived from l-tryptophan. Compounds with high potency versus PDE5 were then evaluated for inhibitory activity against other PDEs to assess isozyme selectivity. Compound 5R,11aS-5-(3,4-dichlorophenyl)-2-ethyl-5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)dione 14 showed a selectivity index of >200 for cGMP hydrolysis by PDE5 versus PDE11. Meanwhile, 6R,12aR-6-(2,4-dichlorophenyl)-2-ethyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4dione 45 demonstrated strong potency for inhibition of PDE11 with an IC(50) value of 11 nM, representing the most potent PDE11 inhibitor thus far reported. Docking experiments differentiated between active and inactive analogues and revealing the conformational, steric, and lipophilic necessities for potent PDE5 inhibition. Many derivatives, including potent PDE5 inhibitors, were able to inhibit the growth of the MDA-MB-231 breast tumor cell line with low micromolar potency.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.
authors.forename: Heba A
authors.initials: HA
authors.lastname: Mohamed
authors.forename: Nancy M R
authors.initials: NM
authors.lastname: Girgis
authors.forename: Rainer
authors.initials: R
authors.lastname: Wilcken
authors.forename: Matthias R
authors.initials: MR
authors.lastname: Bauer
authors.forename: Heather N
authors.initials: HN
authors.lastname: Tinsley
authors.forename: Bernard D
authors.initials: BD
authors.lastname: Gary
authors.forename: Gary A
authors.initials: GA
authors.lastname: Piazza
authors.forename: Frank M
authors.initials: FM
authors.lastname: Boeckler
authors.forename: Ashraf H
authors.initials: AH
authors.lastname: Abadi
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002243:Carbolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D058986:Phosphodiesterase 5 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D002243:Carbolines; D058986:Phosphodiesterase 5 Inhibitors; D011994:Recombinant Proteins