Walcimar T. Vellasco Junior

An Overview on the Development of New Potentially Active Camptothecin Analogs Against Cancer

Camptothecin (CPT) and its derivatives comprise an important group of heterocyclic compounds that are well recognized for their anticancer activities. Efforts have been made over the years aiming to develop new CPT analogs with better clinical efficacy, improved pharmacokinetic profile and lower toxicity. First generation of analogs, irinotecan (CPT-11) and topotecan (TPT) was approved for use by FDA in 1996 for the treatment of colorectal (CPT-11) and cervical, ovarian and small lung cancers (TPT). Other analogs of CPT are currently in different phases of clinical trials. As CPT represents an important lead compound in the field of antitumor- research, in this review we will highlight some recent discoveries (2008-2013) on the development of novel camptothecin-based compounds as potential anticancer agents.

Microwave-Assisted Synthesis of 1,3-Thiazolidin-4-ones and 2-Aryl-1,3-oxathiolan-5-ones

A microwave-enhanced, rapid, three-component one-pot condensation method has been developed for the synthesis of 1,3-thiazolidin-4-ones using toluene in open vessels at atmospheric pressure. Applying this methodology, eleven 1,3-oxathiolan-5-ones were also synthesized in good yields. Thiazolidinones belong to an important group of heterocyclic compounds possessing diverse biological activities such as insecticidal, anticonvulsant, tuberculostatic, antiinflammatory, antiviral, etc. [1]. The anti-HIV biological activity of thiazolidinones has been associated with the ability to assume “butterfly-like” conformation [2-4]. These compounds have been previously prepared from three components (an aldehyde, an amine and mercapto acetic acid), by various oneand two-step syntheses [1]. Such reactions have also been carried out using microwave irradiation [5,6]. The reactions proceed by initial imine formation, which undergoes attack by the sulfur nucleophile, followed by intramolecular cyclization on elimination of water. The most common protocol to remove the water is by azeotropic distillation. Recently we published the formation of 4thiazolidinones by cyclocondensation reactions of an aminoacid, arenealdehydes and mercaptoacetic acid in moderate to good yields [7-9]. In the current work, we studied the formation of these heterocycles using microwave irratiation. *Address correspondence to this author at the Instituto de Tecnologia em Farmacos – Farmanguinhos FIOCRUZ. R. Sizenando Nabuco 100, Manguinhos, 21041-250, Rio de Janeiro-RJ, Brazil; E-mail: wjcunico@far.fiocruz.br Microwave irradiation is an alternative heating method based on the ability of compounds to transform electromagnetic energy into heat. This method, which can increase chemical reaction rates, yields and can form cleaner products, can be sucessfully applied in pharmaceutical chemistry [10,11]. Considering that MW irradiation using commercial domestic ovens has been recently used to accelerate organic reactions [12-14], we have compared the results of formation of 1,3-thiazolidin-4-ones and 1,3-oxathiolan-5-ones performed by the microwave-assited method and conventional procedures. The 1,3-thiazolidin-4-ones were synthesized from the reaction of arenealdehydes and valine with an excess of mercaptoacetic acid, using toluene in microwave oven, for six minutes (Scheme 1). When the nitrobenzaldehydes were used, the major products were 2-aryl-3-benzyl-1,3thiazolidin-4-ones 2a-c in excellent yields (Table 1). However, when 4-methoxyben-zaldehyde (entry 5) and 4fluorobenzaldehyde (entry 4) were used as precursors, a mixture of heterocycles 2, 3 and 4 was detected by GC and their separation was difficult due to similar retention times as stated in previous works (Table 1) [7,8]. CHO

Synthesis and Antimycobacterial Activity of 2-aryl-3-(arylmethyl)-1,3- thiazolidin-4-ones

Fifteen new heterocyclic thiazolidinones have been synthesized from one-pot reactions of piperonylamine, are- nealdehydes and mercaptoacetic acid. These compounds plus ten 2-aryl-3-(benzyl)-1,3-thiazolidin-4-ones which had been previously synthesized, were evaluated as antibacterial agents against Mycobacterium tuberculosis H37Rv using the Alamar Blue susceptibility test and their activity expressed as the minimum inhibitory concentration (MIC) in μg/mL. Six of the series exhibited modest activity when compared to the first line drugs such as isoniazid (INH) and rifampicin (RIP). Therefore this class of compounds could be a good starting point to develop new lead compounds in the treatment of multi-drug resistant tuberculosis.

Synthesis and biological evaluation of novel 6-hydroxy-benzo[d][1,3]oxathiol-2-one Schiff bases as potential anticancer agents.

With the aim of discovering new anticancer agents, we have designed and synthesized novel 6-hydroxy-benzo[d][1,3]oxathiol-2-one Schiff bases. The synthesis started with the selective nitration at 5-position of 6-hydroxybenzo[d][1,3]oxathiol-2-one (1) leading to the nitro derivative 2. The nitro group of 2 was reduced to give the amino intermediate 3. Schiff bases 4a–r were obtained from coupling reactions between 3 and various benzaldehydes and heteroaromatic aldehydes. All the new compounds were fully identified and characterized by NMR (1H and 13C) and specifically for 4q by X-ray crystallography. The in vitro cytotoxicity of the compounds was evaluated against cancer cell lines (ACP-03, SKMEL-19 and HCT-116) by using MTT assay. Schiff bases 4b and 4o exhibited promising cytotoxicity against ACP-03 and SKMEL-19, respectively, with IC50 values lower than 5 μM. This class of compounds can be considered as a good starting point for the development of new lead molecules in the fight against cancer.

Synthesis and antimalarial activity of thioetherhydroxyethylsulfonamides, potential aspartyl protease inhibitors, Part 3

A series of novel thioetherhydroxyethylsulfonamide derivatives has been synthesized from the coupling of intermediates 3-amino-4-phenyl-1-thioetherazine-butan-2-oles 6,7 with arenesulfonyl chlorides in good yields. Characterizations of products were achieved by NMR techniques and specifically for compound 8e by X-ray crystallography. Preliminary results of antimalarial activity in vitro against the Plasmodium falciparum W2 clone (chloroquine resistant and mefloquine sensitive) showed moderate activity for hydroxyethylsulfonamide 8f. In addition, none of the compounds tested showed cytotoxicity at high concentration tested against HepG2 and BGM cell lines.

Crystallographic and computational study of t-butyl N-[3-hydroxy-1-phenyl-4-(pyridin- 2-ylsulfanyl)butan-2-yl]carbamate and its pyrimidin-2-yl analogue

Abstract The crystal structure analysis of the biologically-relevant title compound (1) shows the carbonyl-O2 and amide-H atoms to be anti, and perpendicular relationships between the carbamate residue and the pyridyl ring [dihedral angle=84.60(10)°] and between the carbamate and aryl ring [74.84(11)°]; the rings are approximately co-planar [12.07(17)°]. An intramolecular hydroxyl-O–H···N(pyridyl) hydrogen bond that closes a S(7) loop is noted. Of interest is the observation that this hydrogen bond is not found in the structure of the pyrimidinyl analogue (2) which was characterised as a monohydrate, i.e. 2·H2O, in an earlier study. Density-functional theory calculations show the observed conformation in 1 is 2.0 kcal/mol more stable than the conformation where the intramolecular hydrogen bond is absent. This energy difference reduces to ca 0.5 kcal/mol in the case of 2. The differences in molecular conformations found for 1 and 2 are therefore ascribed to the dictates of overall molecular packing, in particular due to the influence of lattice water in 2·H2O.

Antibacterial Activity of Thioetherhydroxyethylsulfonamide Derivatives

Thioetherhydroxyethylsulfonamide derivatives were synthesized and evaluated for their in vitro antibacterial activity against Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853) and Staphylococcus aureus (ATCC 25923). Results have shown that compounds 8c and 9e display potent activity (MIC = 0.125 µg/mL) against E. coli when compared with the standard drug sulfamethoxazole (SMZ, MIC < 0.5 µg/mL) for this same strain. All the new compounds were fully identified and characterized by NMR ((1)H and (13)C) and X-ray crystallography (for compound 8c). This class of compounds can be considered as a good starting point for the development of new lead molecules in the fight against multi-drug bacterial resistance.

N-{(2S)-3-Hy­droxy-4-[(5-methyl-1,3,4-thia­diazol-2-yl)sulfan­yl]-1-phenyl-2-but­yl}-4-methyl­benzene­sulfonamide

The thiadiazoyl and sulfonyl-benzene rings in the title compound, C20H23N3O3S3, are aligned to the same side of the molecule, forming a twisted ‘U’ shape [dihedral angle = 77.6 (5)°]. The benzyl-benzene ring is orientated in the opposite direction from the molecule but projects approximately along the same axis as the other rings [dihedral angle between benzene rings = 28.2 (5)°] so that, overall, the molecule has a flattened shape. The hydroxy and amine groups are almost syn which enables the formation of intermolecular hydroxy-OH⋯N(thiadiazoyl) and amine-H⋯O(sulfonyl) hydrogen bonds leading to a supramolecular chain aligned along the a axis.