Adão A. Sabino

Calixarenes as New Platforms for Drug Design

Calixarenes, macrocyclic compounds of phenolic units linked by methylene groups at the 2,6-positions, present some of the requirements to serve as platforms for the design and synthesis of biological active compounds. They are also interesting host molecules for chemical biology study purposes. Their basic molecular scaffold has potential ability for molecule recognition; it is promptly synthesized in large amounts, and might be easily modified for maximizing molecular interactions toward relevant guest molecules. Calixarenes present well-defined conformational properties and cavities with molecular dimensions that enable to encapsulate guest drugs. Calixarenes have been shown to have antiviral, antibacterial, antifungal, and anticancer activities (including HIV as target). We provide here an overview of the use of calixarenes either as new chemical entity of distinct biological activities or as host for bioactive guest molecules. The importance of calixarenes for drugs development is discussed. The use of Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS) techniques for the study of calixarenes as biological molecule hosts is also described.

Free radical scavenging and antiproliferative properties of Biginelli adducts.

A series of Biginelli adducts bearing different substituents at C-4 position were synthesized by using p-sulfonic acid calix[4]arene as a catalyst. The in vitro potential to scavenge reactive nitrogen/oxygen species (RNS and ROS) and the ability to inhibit cancer cells growth were then investigated. Four adducts were found to be potent scavengers of 2,2-diphenyl-1-picrylhydrazyl (RNS) and/or superoxide anion (ROS) radicals. The antiproliferative activity against cancer cells was disclosed for the first time for 16 monastrol analogs. The capacity of all compounds to inhibit cancer cells growth was dependent on the histological origin of cells, except for BA24, which was highly active against all cell lines. BA20 and BA33 were as potent as the reference drug doxorubicin against adriamycin-resistant ovarian and prostate cancer cells, respectively. These results highlight some monastrol analogs as lead compounds for the design of new free radical scavengers and anticancer agents.

Total synthesis of (+)-herbarumin I via intermolecular Nozaki-Hiyama-Kishi reaction

Abstract The phytotoxin herbarumin I, isolated from Phoma herbarum , was stereoselectively synthesized in 17 steps and 6% yield from l -arabinose featuring the intermolecular Nozaki–Hiyama–Kishi coupling and modified Yamaguchi macrolactonization as key steps.

Efficient synthesis of 2,4-disubstituted quinolines: calix[n]arene-catalyzed Povarov-hydrogen-transfer reaction cascade

A cascade process involving the Povarov reaction and hydrogen transfer catalyzed with p-sulfonic acid calix[4]arene was disclosed and afforded the synthesis of 2,4-disubstituted quinolines in good yields under appropriate conditions in a single pot process.

“Dba-free” palladium intermediates of the Heck–Matsuda reaction

The dba-free Heck-Matsuda reaction was investigated via direct ESI-MS(/MS) monitoring. Palladium species involved in the reduction of Pd(II) during a Wacker type reaction and several dba-free arylpalladium transient complexes were detected and characterized. Based on these findings, a more comprehensible catalytic cycle for this pivotal reaction is suggested.

Synthesis of aryl aldimines and their activity against fungi of clinical interest.

Aldimines are aldehyde‐derived compounds that contain a C=N group. Besides its broad industrial applications, this class of non‐naturally occurring compounds are found to possess antibacterial, antifungal, antimalarial, antiproliferative, anti‐inflammatory, antiviral, and antipyretic properties. Based on this, six aryl aldimines were synthesized from the condensation of aromatic amines with benzaldehydes. The antifungal activities of synthesized compounds were evaluated against nineteen fungal strains that included Candida and Aspergillus species, Cryptococcus neoformans. The aryl aldimines 2‐(benzylideneamino)phenol (3) and 4‐(benzylideneamino)phenol (8) were the most active compounds against the fungi studied. Compounds 3 and 8 efficiently inhibited the metabolism of C. neoformans mature biofilm.

Gas phase chemistry of the 2-tert-butyl-3-phenylphosphirenylium cation: novel onium ions by nucleophilic attack at phosphorus and de novo P-spiro bicyclic phosphonium ions via[4 + 2+] cycloaddition with dienes

The 2-tert-butyl-3-phenylphosphirenylium ion 13 is formed in abundance in the gas phase from 1-chloro-1H-phosphirene 6 upon 70 eV electron ionization. Collision-induced dissociation (CID) and ion-molecule reactions followed by CID of the product ions were performed via pentaquadrupole mass spectrometry to probe the structure and reactivity of 13 towards representative nucleophiles and dienes. Under CID conditions, 13 produces a variety of fragment ions mainly via dissociation processes that are preceded by isomerizations. In ion-molecule reactions, 13 reacts readily with ethers, sulfides, pyridine and aniline to form hitherto unknown oxonium, sulfonium and azonium ions via nucleophilic attack at phosphorus. With butadiene, isoprene, 1-acetoxybutadiene, and with Danishefskys diene (1-methoxy-3-silyloxybuta-1,3-diene), 13 undergoes [4 + 2+] cycloaddition at phosphorus to generate novel P-spiro bicyclic phosphonium ions. With butadiene and isoprene, a second [4 + 2] cycloaddition occurs which generates P-spiro tricyclic phosphonium ions. Whereas 13 also reacts readily with 1-acetoxybutadiene via[4 + 2+] cycloaddition, most of the nascent P-spiro cycloadducts are unstable and dissociate by the loss of either a neutral ketene or acetic acid molecule. B3LYP/6-31G(d,p) calculations were performed to gain insight into the structures of the product ions. The present study constitutes the first successful attempt to unravel the chemistry of 13, a unique 2 pi-Hückel phosphirenylium ion for which no direct solution chemical reactivity data are as yet available. The present findings also create a parallel with the solution reactivity of 1-halo-1H-phosphirenes and 1-triflato-1H-phosphirenes as precursors to phosphirenylium ions.

Organocatalysis in the Three-Component Povarov Reaction and Mechanistic Investigation by Mass Spectrometry

The advent of organocatalysis brought the prospect of a complementary mode of catalysis, with the potential for savings in cost, time and energy. 1 In this work p-sulfonic acid calix[4]arene (CX4SO3H) was employed as a organocatalyst to promote a threecomponent Povarov reaction, for the preparation of julolidines. 2 Julolidines and derivatives are endowed with interesting scientific and industrial applications. 3