Cosmas O. Okoro

Novel fluorinated acridone derivatives. Part 1: synthesis and evaluation as potential anticancer agents.

We report on the synthesis of a novel series of fluorinated acridones from 5-trifluoromethyl-1,3-cyclohexanedione. The cytotoxic activities of the compounds were studied in several cancer cells. Compounds 9a, 9c, 9e, 9f, and 9h exhibited significant anticancer activities in selected cell lines. Compound 9c is the most active showing GI(50) that ranged in values from 0.13 to 26 microM, covering a wide range of cancer cell lines.

Synthesis and in vitro cytotoxicity evaluation of some fluorinated hexahydropyrimidine derivatives.

A series of trifluoromethylated hexahydropyrimidine and tetrahydropyrimidine derivatives were synthesized and their in vitro cytotoxic activities were determined in colon cancer cell line (COLO 320 HSR). Compounds 4f, 4g, 4k, 5, and 7 proved to be the most active in this series of compounds. They represent promising new leads for the development of highly potent and selective anticancer compounds. All the compounds are lipophilic due to the trifluoromethyl group, and are thus expected to penetrate the membrane in appreciable concentration.

In vitro anticancer screening of 24 locally used Nigerian medicinal plants

BackgroundPlants that are used as traditional medicine represent a relevant pool for selecting plant candidates that may have anticancer properties. In this study, the ethnomedicinal approach was used to select several medicinal plants native to Nigeria, on the basis of their local or traditional uses. The collected plants were then evaluated for cytoxicity.MethodsThe antitumor activity of methanolic extracts obtained from 24 of the selected plants, were evaluated in vitro on five human cancer cell lines.ResultsResults obtained from the plants screened indicate that 18 plant extracts of folk medicine exhibited promising cytotoxic activity against human carcinoma cell lines. Erythrophleum suaveolens (Guill. & Perr.) Brenan was found to demonstrate potent anti-cancer activity in this study exhibiting IC50 = 0.2-1.3 μg/ml.ConclusionsBased on the significantly potent activity of some plants extracts reported here, further studies aimed at mechanism elucidation and bio-guided isolation of active anticancer compounds is currently underway.

Preparation of O-(Silyl)benzyl Alcohols

Abstract Abstract: γ-Hydroxysilanes 4 can be easily prepared from bromosilyl ethers 3 by a reaction involving 1,4-migration of the silicon group from oxygen to carbon.

CoMFA and CoMSIA studies on fluorinated hexahydropyrimidine derivatives

3D-QSAR models of a series of fluorinated hexahydropyrimidine derivatives with cytotoxic activities have been developed using CoMFA and CoMSIA. These models provide a better understanding of the mechanism of action and structure-activity relationship of these compounds. By applying leave-one-out (LOO) cross validation study, the best predictive CoMFA model was achieved with 3 as the optimum number of components, which gave rise to a non-cross-validated r(2) value of 0.978, and standard error of estimate of 0.059, and F value of 144.492. Similarly, the best predictive CoMSIA model was derived with 4 as the number of components, r(2) value of 0.999, F value of 4381.143, and standard error of estimate, 0.011. The above models will inspire the design and synthesis of novel hexahydropyrimidines with enhanced potency and selectivity.

Conformational Analysis and Molecular Properties of N-(Substituted Phenylcarbonylamino)- 4-(1-Hydroxymethylphenyl)-1,2,3,6-Tetrahydropyridines

The three-dimensional structures of active derivatives of N-(substitutedphenylcarbonylamino)-4-(1-hydroxymethylphenyl)-1,2,3,6-tetrahydropyri-dines, which have previously been shown to possess anti-inflammatory activities, were built using BIOMEDCAche 5.0 software program. In addition, the three dimensional structures of some of the inactive ones were similarly generated. The conformational analysis, molecular and electronic structures were examined by molecular mechanics and quantum mechanics calculations. The primary objective was to clarify the effects of physicochemical properties of substituents on activity, since the exact role of the substitution pattern on the phenyl ring is uncertain. In addition, the experimental log P values did not appear to have any influence on the anti-inflammatory potencies of these compounds, since compounds having differing lipid solubilities are equiactive. We found that strongly electron-donating group, such as the para-substituted methoxy group, detracts from activity. The conformational analysis indicated that the 4-ethyl derivative had the lowest energy conformation. Except for compound 1, which showed the lowest surface volume, compounds 2-9 had nearly similar surface volumes.

The Synthesis Of Several N-(Substituted Phenylcarbonylamino)-4-(3-cyclohexenyl)-1,2,3,6-tetrahydropyridines as Potential Anti-Inflam-Matory Agents

Several N-(substituted phenylcarbonylamino)-4-cyclohexenyl-1,2,3,6-tetrahydropyridines 7 were synthesized via sodium borohydride reduction of the corresponding N-(substituted phenylcarbonylimino)-4...

Novel trifluoromethylated 9-amino-3,4-dihydroacridin-1(2H)-ones act as covalent poisons of human topoisomerase IIα

A number of topoisomerase II-targeted anticancer drugs, including amsacrine, utilize an acridine or related aromatic core as a scaffold. Therefore, to further explore the potential of acridine-related compounds to act as topoisomerase II poisons, we synthesized a series of novel trifluoromethylated 9-amino-3,4-dihydroacridin-1(2H)-one derivatives and examined their ability to enhance DNA cleavage mediated by human topoisomerase IIα. Derivatives containing a H, Cl, F, and Br at C7 enhanced enzyme-mediated double-stranded DNA cleavage ∼5.5- to 8.5-fold over baseline, but were less potent than amsacrine. The inclusion of an amino group at C9 was critical for activity. The compounds lost their activity against topoisomerase IIα in the presence of a reducing agent, displayed no activity against the catalytic core of topoisomerase IIα, and inhibited DNA cleavage when incubated with the enzyme prior to the addition of DNA. These findings strongly suggest that the compounds act as covalent, rather than interfacial, topoisomerase II poisons.

5,7-Dibromo-3-trifluoro-methyl-3,4-dihydro-acridin-1(2H)-one.

In the title compound, C14H8Br2F3NO, the molecule is disordered across an approximate non-crystallographic mirror plane, which is in the plane of the fused ring system [The tetrahedral C atom bearing the trifluormethyl substituent is disordered with site occupancy factors of 0.80 (2) and 0.20 (2)]. In the crystal, a one-dimensional stacking of molecules involves interactions between the pyridine ring and symmetry-related Br and O atoms of adjacent molecules. The stacking distance between the mean planes of adjacent molecules is 3.395 (4) Å.