Adriano Afonso

Synthesis of 3-Arylpropenyl, 3-Arylpropynyl and 3-Arylpropyl 2-Azetidinones as Cholesterol Absorption Inhibitors: Application of the Palladium-Catalyzed Arylation of Alkenes and Alkynes

A series of 3-(3′-arylpropenyl)-2-azetidinones 8a–8k and 3-(3′-arylpropynyl)-2-azetidinones 16m–16p were prepared by the palladium-catalyzed arylation of 3-(3′-propenyl)-2-azetidinone 7, or by arylation of 4-pentenoic acid, or via ethyl 4-pentynoate followed by 2-azetidinone ring construction. The unsaturated 2-azetidinones were transformed to their saturated analogs 9a–9p by catalytic hydrogenation. Azetidinones 8a–8k, 9a–9p, and 16m–16p were evaluated for their biological activity as cholesterol absorption inhibitors in hamsters.

Synthesis and evaluation of pyrazolo[3,4-b]quinoline ribofuranosides and their derivatives as inhibitors of oncogenic Ras

Abstract A series of pyrazolo[3,4-b]quinoline ribofuranosides were prepared using the glycosylation methodology of Vorbruggen. Oxidative cleavage of the ribose moiety in 6 furnished the dialdehyde intermediate 36, which cyclizes upon reductive amination providing the morpholino compound 37. Derivatives from both the ribose and morpholino series were evaluated for their ability to inhibit the nucleotide exchange process of oncogenic Ras. 1a

Novel H3 receptor antagonists. Sulfonamide homologs of histamine

Sulfonamides derived from 4(5)-(omega-aminoalkyl)-1H-imidazoles containing chain lengths of three- to five-carbons were synthesized. Good to moderate H3 receptor binding affinities were observed for several butyl and pentyl homologs, whereas binding affinities were considerably weaker in the propyl series. Separation of the imidazole ring and the sulfonamide unit by a four- or five-carbon tether afforded potent H3 receptor antagonists.

Selective chemical modifications of polymyxin B

Polymyxin B (1) monohydrochloride was converted to the tetra-BOC derivatives 1b and 1c by reaction with di-tert-butyl dicarbonate. The structures of these protected intermediates were established utilizing a degradative sequence that afforded 3 and 5. A method for the deprotection 2,4-dinitrophenylamines to the free amine, utilizing a strongly basic ion-exchange resin, was developed for use in the degradative sequence. The tetra-BOC derivatives 1b and 1c were used to prepare several Polymyxin B derivatives 6-27 at the DAB1 and DAB9-gamma-amine. The antibacterial activity of these selectively functionalized derivatives is reported here.

Synthesis of 3-heterosubstituted isocephem and iso-oxacephem antibiotics

Abstract Triethyl phosphite-induced cyclisation of 1-oxalyl-4-(alkylthio-thionocarbonylthiomethyl or -oxymethyl)-2-azetidinones provides novel 3-alkylthio isocephems and isooxacephems.

Synthesis of Isomeric 3-Piperidinyl and 3-Pyrrolidinyl Benzo[5,6]cyclohepta[1,2-b]pyridines: Sulfonamido Derivatives as Inhibitors of Ras Prenylation

Blocking farnesylation of oncogenic Ras proteins is a mechanism based therapeutic approach that is of current interest for the development of antitumor agents to treat ras associated tumors. As part of a SAR study on the lead farnesyl protein transferase (FPT) inhibitor I, we report here the synthesis of novel geometric isomers II and III and the FPT inhibition activity of their N-acyl and N-sulfonamido derivatives 15-65. The N-acyl derivatives are markedly less active than the lead inhibitor I thereby demonstrating that the spatial location of the N-acyl group in I is critical for binding of the compound to FPT. In contrast to I, the N-sulfonamido-II series is a novel lead of non-sulfhydryl, nonpeptidic compounds that are dual FPT/GGPT inhibitors. In light of recent reports on the alternative prenylation of N- and K-Ras, dual FPT/GGPT inhibitors may be required to control cell proliferation in tumors containing activated Ras.

Beta-lactams derived from the reaction of phenanthridines and 11H-dibenzo[b,e]azepin-11-one with phenylvaleryl chloride. Synthesis of fused analogs of the cholesterol absorption inhibitor Sch 48461

Abstract Phenanthridines 4 and the 11H-dibenzo[b,e]azepin-11-one, 17 were used as the imine components in the ketene-imine β-lactam synthesis to provide the fused tetracyclic β-lactams 7, 8 and 18.

Inhibitors of farnesyl protein transferase. synthesis and biological activity of amide and cyanoguanidine derivatives containing a 5,11-dihydro[1]benzthiepin, benzoxepin, and benzazepin [4,3-b]pyridine ring system

Bioisosteric replacement of the C-6 carbon atom in piperidine I and piperazine II with S, O, and N heteroatoms is described. Amide and cyanoguanidine derivatives of these compounds were evaluated in vitro and found to be good inhibitors of farnesyl-protein transferase. An improved method of preparing the 5,11-dihydro-[1]-benzthiepin nucleus 6 was accomplished in high yield and with excellent regioselectivity using an AlCl3 melt protocol.

Analogues of 1-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo-[5,6]-cyclohepta [1,2-b]pyridin-11-yl)piperidine as inhibitors of farnesyl protein transferase.

The synthesis of several 4-pyridylacetyl N-oxide derivatives of 4-(3-bromo-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]-pyridin-11-yl)pi perazine/piperidine 3 is described. This study was aimed at identifying fomesyl protein transferase (FPT) inhibitors in these two series of tricycles containing different phenyl ring substituents. The in vitro activity profile of the initial group of compounds 7a-7g led to the synthesis of the 8-methyl-10-methoxy and 8-methyl-10-bromo analogues 7i, 13i, and 13j. The 11R(-) enantiomers of these compounds were found to exhibit potent in vitro FPT inhibition activity.

Synthesis of a C11 spirocyclopropyl derivative of 8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2b]pyridine

Abstract The carbanion derived from 8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b] pyridine ( 3 ) reacts with methyl acrylate to form the C 11 spirocyclopropane carboxylic acid methyl ester 6 . Compound 6 was converted in five steps to the N-methyl 2′-ethylamino spirocyclopropane 2 (R=H) which was required for a structure-activity study based on the lead Farnesyl Protein Transferase inhibitor 1 .