1. Synthesis and anticancer activity of 5-(3-indolyl)-1,3,4-thiadiazoles
Dalip Kumar, N Maruthi Kumar, Kuei-Hua Chang, Kavita Shah Eur J Med Chem. 2010 Oct;45(10):4664-8. doi: 10.1016/j.ejmech.2010.07.023. Epub 2010 Jul 21.
A series of 5-(3-indolyl)-2-substituted-1,3,4-thiadiazoles 5a-m were synthesized and their cytotoxicity analyzed against six human cancer cell lines. The reaction of indole-3-carboxylic acid 3 with aryl or heteroaryl hydrazides afforded the N,N'-diacylhydrazines 4, which upon treatment with Lawesson's reagent resulted in the formation of indolyl-1,3,4-thiadiazoles 5a-m in good yields. Indolyl-1,3,4-thiadiazole 5m with 4-benzyloxy-3-methoxyphenyl and 5-bromo indolyl substituents is the most active in suppressing the growth of cancer cells (IC(50) 1.5 muM, PaCa2). The compounds 5b, 5e and 5h bearing C-2 substituent as benzyl, 3,4-dimethoxyphenyl and 4-benzyloxy-3-methoxyphenyl, respectively, have shown significant cytotoxicity against multiple cancer cell lines. Introduction of 4-dimethylamino (5d and 5k) and 3,4,5-trimethoxy (5l) groups in the C-2 phenyl ring induced selectivity against MCF7 and MDA-MB-231 cancer cell lines (compounds 5d, 5k and 5l).
2. Synthesis of 4-substituted 3,3-difluoropiperidines
Riccardo Surmont, Guido Verniest, Jan Willem Thuring, Gregor Macdonald, Frederik Deroose, Norbert De Kimpe J Org Chem. 2010 Feb 5;75(3):929-32. doi: 10.1021/jo902164z.
Synthetic strategies toward 4-substituted 3,3-difluoropiperidines were evaluated. 4-Alkoxymethyl- and 4-aryloxymethyl-3,3-difluoropiperidines were synthesized via 1,4-addition of ethyl bromodifluoroacetate to 3-substituted acrylonitriles in the presence of copper powder, followed by borane reduction of the cyano substituent, lactamization, and reduction of the lactam. This method was applied to establish the synthesis of N-protected 3,3-difluoroisonipecotic acid, a fluorinated gamma-amino acid. 4-Benzyloxy-3,3-difluoropiperidine was prepared using an analogous methodology and was converted to N-protected 3,3-difluoro-4,4-dihydroxypiperidine, a compound with high potential as a building block in medicinal chemistry.
3. Salmeterol Xinafoate
Manal M Anwar, Radwan S El-Haggar, Wafaa A Zaghary Profiles Drug Subst Excip Relat Methodol. 2015;40:321-69. doi: 10.1016/bs.podrm.2015.02.002. Epub 2015 Apr 1.
Salmeterol xinafoate is a potent and a long-acting β2-adrenoceptor agonist. It is prescribed for the treatment of severe persistent asthma and chronic obstructive pulmonary disease. Different methods were used to prepare (R)-(-)-salmeterol such as: mixing a sample of 4-benzyloxy-3-hydroxymethyl-ω-bromoacetophenone with sodium lauryl sulfate and the mixture was added to the microbial culture of Rhodotorula rubra, treatment of p-hydroxyacetophenone with Eschenmoser's salt and carbonate exchange resin followed by a sequence of supported reagents and scavenging agents or via Rh-catalyzed asymmetric transfer hydrogenation. The enantioselective synthesis of (S)-salmeterol was achieved via asymmetric reduction of the azidoketone 4 by Pichia angusta yeast. Physical characteristics of salmeterol xinafoate were confirmed via: X-ray powder diffraction pattern, thermal analysis and UV, vibrational, nuclear magnetic resonance, and mass spectroscopical data. Initial improvement in asthma control may occur within 30 min following oral inhalation of salmeterol in fixed combination with fluticasone propionate. Clinically important improvements are maintained for up to 12 h in most patients. It is extensively metabolized in the liver by hydroxylation, thus increased plasma concentrations may occur in patients with hepatic impairment.
