Edson dos Anjos dos Santos

Synthesis and evaluation of diaryl sulfides and diaryl selenide compounds for antitubulin and cytotoxic activity

We have devised a procedure for the synthesis of analogs of combretastatin A-4 (CA-4) containing sulfur and selenium atoms as spacer groups between the aromatic rings. CA-4 is well known for its potent activity as an inhibitor of tubulin polymerization, and its prodrugs combretastatin A-4 phosphate (CA-4P) and combretastatin A-1 phosphate (CA-1P) are being investigated as antitumor agents that cause tumor vascular collapse in addition to their activity as cytotoxic compounds. Here we report the preparation of two sulfur analogs and one selenium analog of CA-4. All synthesized compounds, as well as several synthetic intermediates, were evaluated for inhibition of tubulin polymerization and for cytotoxic activity in human cancer cells. Compounds 3 and 4 were active at nM concentration against MCF-7 breast cancer cells. As inhibitors of tubulin polymerization, both 3 and 4 were more active than CA-4 itself. In addition, 4 was the most active of these agents against 786, HT-29 and PC-3 cancer cells. Molecular modeling binding studies are also reported for compounds 1, 3, 4 and CA-4 to tubulin within the colchicine site.

Diaryl sulfide analogs of combretastatin A-4: Toxicogenetic, immunomodulatory and apoptotic evaluations and prospects for use as a new chemotherapeutic drug.

Combretastatin A-4 exhibits efficient anti-cancer potential in human tumors, including multidrug-resistant tumors. We evaluated the mutagenic, apoptotic and immunomodulatory potential of two diaryl sulfide analogs of combretastatin A-4, 1,2,3-trimethoxy-5-([4-methoxy-3-nitrophenyl]thio)benzene (analog 1) and 1,2,3-trimethoxy-5-([3-amino-4-methoxyphenyl]thio)benzene (analog 2), as well as their association with the anti-tumor agent cyclophosphamide, in Swiss mice. Such evaluation was achieved using the comet assay, peripheral blood micronucleus test, splenic phagocytosis assay, and apoptosis assay. Both analogs were found to be genotoxic, mutagenic and to induce apoptosis. They also increased splenic phagocytosis, although this increase was more pronounced for analog 2. When combined with cyclophosphamide, analog 1 enhanced the mutagenic and apoptotic effects of this anti-tumor agent. In contrast, analog 2 did not enhance the effects of cyclophosphamide and prevented apoptosis at lower doses. These data suggest that analog 1 could be an adjuvant chemotherapeutic agent and possibly improve the anti-neoplastic effect of cyclophosphamide. Additionally, this compound could be a candidate chemotherapeutic agent and/or an adjuvant for use in combined anti-cancer therapy.

Synthesis Method for Thiosulfonate and Report of Its Insecticidal Activity in Anagasta kuehniella (Lepidoptera: Pyralidae)

Insect pests have caused economic losses valued at billions of dollars in agricultural production. Anagasta kuehniella (Zeller), the Mediterranean flour moth, is of major economic importance as a flour and grain feeder and is often a severe pest in flourmills. This study provides a suitable route for the direct preparation of thiosulfonates 2 and 3 from thiols, under mild conditions, with good yields; these thiosulfonates were tested for their regulatory effect on insect growth. The chronic ingestion of thiosulfonates resulted in a significant reduction in larval survival and weight. In addition, the tryptic activity of larvae was sensitive to these thiosulfonates. Results suggest that thiosulfonates 2 and 3 have a potential antimetabolic effect when ingested by A. kuehniella. The use of AgNO3/BF3·OEt2 and Al(H2PO4)3/HNO3 provides a suitable route for the direct preparation of thiosulfonates from thiols under mild conditions with good yields. These thiosulfonates were toxic for A. kuehniella larvae, suggesting their potential as biotechnological tools.

Synthesis and biological activity of sulfur compounds showing structural analogy with combretastatin A-4

We extended our previous exploration of sulfur bridges as bioisosteric replacements for atoms forming the bridge between the aromatic rings of combretastatin A-4. Employing coupling reactions between 5-iodo-1,2,3-trimethoxybenzene and substituted thiols, followed by oxidation to sulfones with m-CPBA, different locations for attaching the sulfur atom to ring A through the synthesis of nine compounds were examined. Antitubulin activity was performed with electrophoretically homogenous bovine brain tubulin, and activity occurred with the 1,2,3-trimethoxy-4-[(4-methoxyphenyl)thio]benzene (12), while the other compounds were inactive. The compounds were also tested for leishmanicidal activity using promastigote forms of Leishmania braziliensis (MHOM/BR175/M2904), and the greatest activity was observed with 1,2,3-trimethoxy-4-(phenylthio)benzene (10) and 1,2,3-trimethoxy-4-[(4-methoxyphenyl) sulfinyl]benzene (15).

Synthesis and biological evaluation of biaryl analogs of antitubulin compounds

This paper reports the synthesis of methanones and esters bearing different substitution patterns as spacer groups between aromatic rings. This series of compounds can be considered phenstatin analogs. Two of the newly synthesized compounds, 5a and 5c, strongly inhibited tubulin polymerization and the binding of [(3)H] colchicine to tubulin, suggesting that, akin to phenstatin and combretastatin A-4, they can bind to tubulin at the colchicine site.

Synthesis of resorcinolic lipids bearing structural similarities to cytosporone A

Inspired by the structure and biological activities of resorcinolic lipids and, particularly cytosporone A- a potent inhibitor of plantule germination and growth, we have performed the synthesis of the analogs 3-heptyl-3-hydroxy-5,7-dimethoxy-2-benzofuran-1(3H)-one (1) and 3-heptyl-3-hydroxy-4,6-dimethoxy-2-benzofuran-1(3H)-one (2). The intermediates and products were submitted to allelopathic test using Lactuca sativa L. seeds. Target compound 1 showed an inhibitory effect on germination and growth of hypocotyl and radicle in milimolar range.

A potent larvicidal agent against Aedes aegypti mosquito from cardanol

Cardanol is a constituent of Cashew Nut Shell Liquid that presents larvicidal activity against Aedes aegypti. The isolation of cardanol is somewhat troublesome, however, in this work we describe an efficient and inexpensive method to obtain it as a pure material. The compound was used as starting material to make chemical transformation leading to saturated cardanol, epoxides and, halohydrins. These derivatives were tested for toxicity against Aedes aegypti larvae. The results showed that iodohydrins are very promising compounds for making commercial products to combat the vector mosquito larvae presenting a LC50 of 0.0023 ppm after 72 h of exposure.

Ozonolysis of neem oil: preparation and characterization of potent antibacterial agents against multidrug resistant bacterial strains

Neem, Azadirachta indica A. Juss, is endowed with relevant biological properties and its oil contains unsaturated fatty acids that are susceptible to structural modification by oxidative processes such as ozonolysis to form peroxides. Therefore, the aim of this work was the synthesis, physicochemical characterization, study of thermal behavior, and evaluation of the antimicrobial potential of neem ozonated oils. The ozonolysis reaction was performed over different periods of time, in the presence or absence of water at an ozone concentration of 63 mg L−1 O3/O2. The samples were characterized by 1H and 13C NMR spectroscopy, acid and iodine values and, DSC and TG/DTG thermal analyses. Additionally, quantitative 1H NMR spectroscopy was a very successful and useful tool to determine the unsaturation degree of samples. The products showed excellent broad-spectrum antimicrobial activity in comparison to other ozonated oils reported in the literature, with an MIC of <0.5 mg mL−1 for standard E. faecalis and clinical vancomycin resistant E. faecium, 5.0 mg mL−1 for clinical multiresistant K. pneumoniae (KPC), 2 mg mL−1 for standard S. aureus, and 3 mg mL−1 for methicillin-resistant S. aureus (MRSA). This is the first report on the antimicrobial action of neem oil after the ozonation process. The ozonated neem oils were investigated for their cytotoxicity against two normal human cell lines (HaCaT and HCEC). And the results show the products possess low toxicity. Our studies suggest the compounds can find potential application in the treatment of chronic wounds and skin infections.

Adulteration and Contamination of Commercial Sap of Hymenaea Species

The Hymenaea stigonocarpa and Hymenaea martiana species, commonly known as “jatobá,” produce a sap which is extracted by perforation of the trunk and is commonly used in folk medicine as a tonic. For this study, the authenticity of commercial samples of jatobá was verified by the identification of the main compounds and multivariate analysis and contamination by microbial presence analysis. The acute toxicity of the authentic jatobá sap was also evaluated. The metabolites composition and multivariate analysis revealed that none of the commercial samples were authentic. In the microbiological contamination analysis, five of the six commercial samples showed positive cultures within the range of 1,700–100,000 CFU/mL and the authentic sap produced no signs of toxicity, and from a histological point of view, there was the maintenance of tissue integrity. In brief, the commercial samples were deemed inappropriate for consumption and represent a danger to the population.

The use of AgNO3/BF3.Et2O and HNO3/Al(H2PO4)3 systems in the synthesis of aryl thiosulfonates

The thiosulfonates are a class of compounds of great industrial importance. It is worth noting that the aryl thiosulfonates present several biological activities. The synthesis of these compounds is known in the literature although; only a few make use of thiols as the sole starting material. This work shows the use of two reaction systems employed for the synthesis of nitrophenols, AgNO 3 /BF 3 .EtO 2 (I) and HNO 3 /Al(H 2 PO 4 ) 3 (II), as an alternative to the preparation of aryl thiosulfonates. The use of system I led to higher yields (72-76%) then system II (56-61%). These methodologies have not been reported before for the synthesis of these compounds and the products were obtained with good purity.