Oladapo Bakare

Studies on PEGylated and Drug-Loaded PAMAM Dendrimers

Three methods were investigated for their suitability for the activation of poly(ethylene glycol) 2000 mono-methyl ether en route to conjugation with dendrimers, using 4-nitrophenylchloroformate as the activator. The use of acetonitrile as a solvent gave the best results. Poly(ethylene glycol) (PEG) grafted polyamidoamine (PAMAM) dendrimers were synthesized and characterized; the use of acetonitrile as a solvent gave the best result. A series of PEG conjugated PAMAM dendrimers with varying degrees of substitution of the dendrimer surface functional group by PEG were prepared. The encapsulation efficiency and the in vitro release characteristics of these PEG conjugated PAMAM dendrimers were studied. The percentage coverage of PAMAM dendrimer surface with PEG had little effect on the encapsulation efficiency but affected the release of methotrexate. IR spectra showed that many of the encapsulated methotrexate molecules were located within the cavity of the dendrimer.

Biological Activities of Emetine

Emetine is a natural product alkaloid from ipecac species. It is one of the main active ingredients in ipecac syrup used as emetic, and has been used extensively in phytomedicine as an antiparasitic drug. It inhibits both ribosomal and mitochondrial protein synthesis and interferes with the synthesis and activities of DNA and RNA. For this reason, it has been a vital tool to pharmacologists and has demonstrated many biological properties, such as antiviral, anticancer, antiparasitic and contraceptive activities. Also, it has been reported to cause the up-regulation and down-regulation of a number of genes. Some synthetic analogs with interesting biological activities have been prepared. This article reviews the biological activities of emetine and some emetine derived molecules.

Synthesis and MEK1 inhibitory activities of imido-substituted 2-chloro-1,4-naphthoquinones.

Mitogen activated protein kinases are of interest as research tools and as therapeutic target for certain physiological disorders. In this study, we found 2-chloro-3-(N-succinimidyl)-1,4-naphthoquinone 6 to be a selective inhibitor of MEK1 with an IC(50) of 0.38 microM. An open-chain homologue, 10, showed selective cytotoxicity against renal cancer in the NCI in vitro tumor screening. Structure-activity relationship study of eight compounds showed the cyclic imido-substituted chloro-1,4-naphthoquinone as more potent and selective MEK1 inhibitors than the open chain homologues. The imido-substituted chloro-1,4-naphthoquinones were synthesized in a straightforward fashion by refluxing 2-amino-3-chloro-1,4-naphthoquinone with the appropriate acid chloride or diacyl dichloride.

Synthesis of 3-[(N-carboalkoxy)ethylamino]-indazole-dione derivatives and their biological activities on human liver carbonyl reductase.

A series of indazole-dione derivatives were synthesized by the 1,3-dipolar cycloaddition reaction of appropriate substituted benzoquinones or naphthoquinones and N-carboalkoxyamino diazopropane derivatives. These compounds were evaluated for their effects on human carbonyl reductase. Several of the analogs were found to serve as substrates for carbonyl reductase with a wide range of catalytic efficiencies, while four analogs display inhibitory activities with IC(50) values ranging from 3-5 microM. Two of the inhibitors were studied in greater detail and were found to be noncompetitive inhibitors against both NADPH and menadione with K(I) values ranging between 2 and 11 microM. Computational studies suggest that conformation of the compounds may determine whether the indazole-diones bind productively to yield product or nonproductively to inhibit the enzyme.

Antitrypanosomal activities and cytotoxicity of some novel imido-substituted 1,4-naphthoquinone derivatives.

The antitrypanosomal activities, cytotoxicity, and selectivity indices of eleven imido-substituted 1,4-naphthoquinone derivatives and nifurtimox have been studied. Compared to nifurtimox (IC50 = 10.67 μM), all the imido-naphthoquinone analogs (IMDNQ1-IMDNQ11) are more potent on Trypanosoma cruzi with IC50 values ranging from 0.7 μM to 6.1 μM (p < 0.05). Studies of the cytotoxic activities of these compounds on a Balb/C 3T3 mouse fibroblast cell line revealed that four of these compounds, IMDNQ1, IMDNQ2, IMDNQ3, and IMDNQ10 displayed selectivity indices of 60.25, 53.97, 31.83, and 275.3, respectively, rendering them significantly (p < 0.05) more selective in inhibiting the parasite growth than nifurtimox (selectivity index = 10.86).

Iterative design of emetine-based prodrug targeting fibroblast activation protein (FAP) and dipeptidyl peptidase IV DPPIV using a tandem enzymatic activation strategy.

There is an urgent need to develop new agents for treating metastatic prostate cancer to overcome multiple drug resistance to the current standard targeted cancer therapy. Emetine is a highly cytotoxic natural product protein synthesis inhibitor, which is toxic to all cell types. Its cytotoxicity can be blocked by derivatizing its N‐2′ position. Thus emetine can be selectively delivered to cancer cells in the region of metastatic cancer as a prodrug that will be activated by an enzyme selectively overexpressed within the metastatic tumor microenvironment. In this work, we convert emetine to a prodrug activatable by the fibroblast activation protein (FAP), a serine protease overexpressed by the carcinoma associated fibroblasts.

N-(3-Bromo-1,4-dioxo-1,4-dihydro-2-naphth-yl)-2-chloro-N-(2-chloro-benzoyl)benzamide.

The title compound, C24H12BrCl2NO4, was synthesized from 2-amino-3-bromo-1,4-naphthoquinone and 2-chlorobenzoyl chloride. The crystal structure shows that each of the chlorophenyl rings is inclined at about 60° to the naphthoquinone ring system. The two chlorophenyl rings adopt a conformation that ensures that chlorine substituents are anti so as to reduce electronic repulsion. An examination of the packing shows close O⋯Br and Cl⋯Cl contacts of 2.947 (2) and 3.346 (1) Å, respectively. In addition, the molecules are linked by weak intermolecular C—H⋯O and C—H⋯Cl interactions.

2-Chloro-3-(4-chloro­benzamido)-1,4-naphthoquinone

The naphthoquinone ring is almost perpendicular [dihedral angle 71.02 (3)°] to the phenyl group of the title compound, C17H9Cl2NO3, while the dihedral angle between the amide group and the 4-chlorophenyl ring is 21.9 (2)°. The conformation of the N—H and C=O bonds are anti to each other. N—H⋯Cl hydrogen bonds link the molecules into chains in the a-axis direction. In addition, these chains are linked by weak intermolecular C—H⋯O interactions.

Novel drug design for Chagas disease via targeting Trypanosoma cruzi tubulin: Homology modeling and binding pocket prediction on Trypanosoma cruzi tubulin polymerization inhibition by naphthoquinone derivatives.

Chagas disease, also called American trypanosomiasis, is a parasitic disease caused by Trypanosoma cruzi (T. cruzi). Recent findings have underscored the abundance of the causative organism, (T. cruzi), especially in the southern tier states of the US and the risk burden for the rural farming communities there. Due to a lack of safe and effective drugs, there is an urgent need for novel therapeutic options for treating Chagas disease. We report here our first scientific effort to pursue a novel drug design for treating Chagas disease via the targeting of T. cruzi tubulin. First, the anti T. cruzi tubulin activities of five naphthoquinone derivatives were determined and correlated to their anti-trypanosomal activities. The correlation between the ligand activities against the T. cruzi organism and their tubulin inhibitory activities was very strong with a Pearsons r value of 0.88 (P value <0.05), indicating that this class of compounds could inhibit the activity of the trypanosome organism via T. cruzi tubulin polymerization inhibition. Subsequent molecular modeling studies were carried out to understand the mechanisms of the anti-tubulin activities, wherein, the homology model of T. cruzi tubulin dimer was generated and the putative binding site of naphthoquinone derivatives was predicted. The correlation coefficient for ligand anti-tubulin activities and their binding energies at the putative pocket was found to be r=0.79, a high correlation efficiency that was not replicated in contiguous candidate pockets. The homology model of T. cruzi tubulin and the identification of its putative binding site lay a solid ground for further structure based drug design, including molecular docking and pharmacophore analysis. This study presents a new opportunity for designing potent and selective drugs for Chagas disease.

N-(3-Bromo-1,4-dioxo-1,4-dihydro-2-naphth-yl)-4-fluoro-N-(4-fluoro-benzo-yl)benzamide.

In the title compound, C24H12BrF2NO4, synthesized from 2-amino-3-bromo-1,4-naphthoquinone and 4-fluorobenzoyl chloride, the two p-fluorophenyl rings are inclined at 73.9 (1) and 73.6 (1)° to the naphthoquinone ring system. The two imido carbonyl O atoms are anti to each other, while the fluorophenyl rings are located opposite each other, connected to the imide group in a funnel-like arrangement. This conformation allows the fluorine groups be oriented slightly away from each other. An examination of the packing shows a close intermolecular F⋯O contact of 2.982 (5) Å and a Br⋯O contact of 2.977 (4) Å. In addition, the molecules are linked by weak intermolecular C—H⋯O and C—H⋯F interactions.