Halina T. Serafinowska

Inhibition of HSV-1 protease by benzoxazinones

Abstract Benzoxazinones have been discovered which are mechanism based inhibitors of HSV-1 protease with micromolar IC 50 values. Formation of a monoadduct consistent with the acyl-enzyme complex was detected by mass spectroscopy. A parallel array synthesis was developed to explore 2-heteroatom substituted SAR.

Phenyl benzenesulfonamides are novel and selective 5-HT6 antagonists: identification of N-(2,5-dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide (SB-357134)

Substituted N-phenyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamides and conformationally restricted analogues have been identified as high affinity and selective 5-HT6 antagonists. Compounds from this series had a range of pharmacokinetic profiles in rat and in general there was a correlation between clearance and CNS penetration. Based on its overall biological profile 2 (SB-357134) was selected for further pre-clinical evaluation.

An acetal group suitable for the protection of 2'-hydroxy functions in rapid oligoribonucleotide synthesis

Abstract The 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl [Ctmp, as in ( 14a )] has an acid lability similar to that of the 4-methoxytetrahydropyran-4-yl (Mthp) protecting group under mild hydrolytic conditions [pH 2–3]; however, under the relatively more drastic conditions required for the complete removal of a 9-phenylxanthen-9-yl (Px) group, the Ctmp protecting group remains virtually intact.

The synthesis of 5-alkoxy and 5-amino substituted thiophenes

Abstract 5-Alkoxythiophenes have been prepared by an extension of the Gewald thiophene synthesis and a novel four component condensation reaction uncovered by which 5-aminothiophenes have been prepared.

Potent selective thienoxazinone inhibitors of herpes proteases

Abstract Thieno[3,2-d]oxazinones are potent, selective, mechanism-based inhibitors of the herpes proteases with good aqueous stability. Specificity between the HSV and CMV proteases varies across the series: compounds 14b and 14c are submicromolar HSV protease inhibitors with modest CMV protease inhibition, 14g is a selective CMV protease inhibitor; and 32 inhibits both enzymes with an IC 50 of about 1 μM.

Solid phase synthesis of the 3′-terminal nonadecaribonucleoside octadecaphosphate sequence of yeast alanine transfer ribonucleic acid

Abstract The rapid synthesis of the 3′-terminal decaribonucleoside nonaphosphate and nonadecaribonucleoside octadecaphosphate sequences of yeast tRNA Ala by the phosphoramidite approach on controlled pore glass is described; the synthetic products were found to be identical to the authentic oligoribonucleotides, prepared by the phosphotriester approach in solution.

Synthesis of the 3′-terminal half of yeast alanine transfer ribonucleic acid (tRNAAla) by the phosphotriester approach in solution. Part 2

The preparation, by the phosphotriester approach in solution, of the 3′-terminal decaribonucleoside nonaphosphate [UpCpGpUpCpCpApCpCpA (48)], nonadecaribonucleoside octadecaphosphate [ApUpUpCpCpGpGpApCpUpCpGpUpCpCpApCpCpA (49)], and heptatriacontaribonucleoside hexatriacontaphosphate [GpGpApGpApGpGpUpCpUpCpCpGpGpTpψpCpGpApUpUpCpCpGpGpApCpUpCpGpUpCpCpApCpCpA (50)] sequences of yeast alanine transfer ribonucleic acid are described. With the exception of the 3′-terminal adenosine residue which was protected as its 2′,3′-O-methoxymethylene [Mm] derivative, the 2′-hydroxy functions were protected with 4-methoxytetrahydropyran-4-yl [Mthp] groups. The 5′-hydroxy functions of intermediate building blocks were protected with 2-(dibromomethyl)benzoyl [Dbmb (2)], 2-(isopropylthiomethoxymethyl)benzoyl [Ptmt (3)] or 9-phenylxanthen-9-yl [Px (4)] groups. The base residue of the adenosine, cytidine, guanosine, uridine, pseudouridine and 5-methyluridine building blocks were protected as in (5), (6), (7), (8), (9), and (10), respectively. Internucleotide linkages were protected with the 2-chlorophenyl group, and the 2,4-dinitrobenzyl (Dnb) group was used for the temporary protection of 3′-phosphodiester functions. The first phosphorylation step (leading to 3′-phosphodiester intermediates) was carried out by treatment with 2-chlorophenyl bis(1,2,4-triazoyl)phosphate (11) in the presence of 1-methylimidazole in tetrahydrofuran followed by triethylamine and water. 1-(Mesitylene-2-sulphonyl)-3-nitro-1,2,4-triazole [MSNT (15)] was used as the condensing agent in the second phosphorylation step. The final unblocking procedure involved treatment with (i)N1,N1,N3,N3-tetramethylguanidinium E-2-nitrobenzaldehyde oximate in dioxane–acetonitrile–water, (ii) concentrated aqueous ammonia, and (iii) 0.01 M hydrochloric acid.

Studies in the Solid Phase Synthesis of Oligo- and Poly-Ribonucleotides

Abstract The solid phase synthesis of the 3′-terminal 10-mer, 19-mer and 37-mer sequences of unmodified yeast tRNAAla is described. The 2′- and 5′-hydroxy functions are protected, respectively, by the 1- (2-fluorophenyl)-4-methoxypiperidin-4-yl [Fpmp (11)] and 9-phenylxan-then-9-yl [px] groups, and 2-cyanoethyl di-isopropylphosphoramidite building blocks are used.

Synthesis and Properties of S-Phosphates of Some Antiviral Acyclonucleosides

Abstract Suitably protected penciclovir, ganciclovir and 9-[3-hydroxy-2-(hydroxymethyl)propoxy]guanine were converted into their iodo-derivatives which in turn were reacted with trisodium thiophosphate to give the corresponding S-phosphates in good yields.

Synthesis and antiviral activity of new phosphonobutoxypurines

Abstract A series of new 9-(4-phosphonobutoxy)purines was synthesized and evaluated as antiviral agents. 9-(4-Phosphonobutoxy)guanine displayed potent and selective activity against HIV-1 in peripheral blood lymphocytes.