Medicinal Chemistry - Volume 7, Issue 1, 2011

A new trinuclear platinum compound [{trans-PtCl(NH3)2}2{trans-Pt(thiazole)2}{H2N(CH2)6NH2}2]Cl3(NO3) has been synthesized and characterized. The activity of the compound against three human ovarian cancer cell lines A2780, A2780cisR and A2780ZD0473R, its cell uptake and level of binding with DNA have been determined. JH5 is found to be less active than cisplatin against parent A2780 cell line but more active than cisplatin against the A2780cisR and A2780ZD0473R resistant cell lines indicated by the lower resistance factors. The results indicate that at the level of its activity JH5 has been better able to overcome mechanisms of resistance operating in A2780cisR and A2780ZD0473R cell lines. JH5 has higher cellular accumulation of platinum than cisplatin in the A2780cisR and A2780ZD0473R resistant cell lines but lower than cisplatin in the parents A2780 cell line. Cisplatin binds with DNA forming mainly bifunctional intrastrand 1,2- Pt(GG) and 1,2-Pt(AG) adducts that cause local bending of DNA strand. In contrast, JH5 is expected to bind with DNA to form mainly interstrand long-range G-Pt..Pt..Pt(G) adducts that would induce more of a global change in DNA conformation.

A new aminoacidic derivative of valproic acid (VPA) has been synthesized and characterized by analytical and spectral data. The rationale for the preparation of such potential antiepileptic agent is based on the observation that chemical combination of the anticonvulsant pharmacophore, VPA with essential aminoacids could afford more effective and less toxic actives. The synthesis, characterization, physico-chemical parameters functional for crossing Blood Brain Barrier of N-valproyl-L-tryptophan (4) are reported. The Log D pH7.4 (0.3) indicates that (4) is adequate to cross biological membranes. Its chemical and enzymatic stability were assessed. The experiments indicate high stability of compound (4) at pH conditions of physiological fluids. Moreover, both in plasma and in cerebral enzymatic environments compound (4) doesn't undergo cleavage after 24 h. The anticonvulsant activity of the new compound was assessed against epileptic burst discharges evoked in vitro in rat hippocampal slices (Seizure like events - SLEs) and compared with that of the widely used VPA. Compound (4), even at the lower tested concentration, when compared to VPA, showed an improved protective effect against hippocampal seizures. The collected data suggest that compound (4) could be considered a very valuable candidate for subsequent in vivo evaluation as new potential antiepileptic drug.

A series of novel imperatorin derivatives were synthesized from commercially available xanthotoxin. The in vitro pharmacological evaluation indicated that all of the compounds possessed potent vasodilatory activity. Among them, compounds (5b), (5d) and (5e) exhibited higher vasdilatory activity (with EC50 values of 0.68 μM, 0.59 μM and 0.49 μM, respectively) than imperatorin (EC50 = 1.12 μM). The program Volsurf was used to predict the derivatives' ADME relevant descriptors. The results suggested that these novel compounds had a potential interest for the development of novel and potent vasorelaxant agents.

EGFR is the cell-surface receptor. Its overexpression or overactivity has been associated with a number of cancers, including breast, lung, ovarian, and anal cancers. Many therapeutic approaches are aimed at the EGFR. A series of 2, 7-diamino-thiazolo [4,5-d] pyrimidine analogues are among the most highly potent and selective inhibitors of EGFR described to date. For in-depth investigation into the structural and chemical features responsible for the binding recognition mechanism concerned, as well as for exploring the binding pocket of these compounds, we performed a series of automated molecular docking operations. It was revealed that the binding site consisted of three main areas (P1, P2 and P3) composed of most of the hydrophobic amino acids able to accommodate the lipophilic arms of the compounds investigated. However, the solvent interface did not make much contribution to the binding of the inhibitors. The presence of residues Met793 and Asp855 may also be responsible for the binding recognition through H-bond interactions, with Phe856 through a T-shape π-π stacking interaction. The interaction model and pharmacophore of EGFR inhibitors were derived that can be successfully used to explain the different biologic activities of these inhibitors. Moreover, the docking results were quite robust as further validated by molecular dynamics. It is anticipated that the findings reported here may provide very useful information or clue for designing effective drugs for the therapeutic treatment of EGFR-related cancer.

Aminopeptidase N (APN) is a ubiquitous enzyme overexpressed on tumor cells and plays an important role in angiogenesis and metastasis of tumor. Bestatin as an effective inhibitor of aminopeptidase N is used for complementary treatment of cancer with other drugs. In this work, we reformed the structure of bestatin to a new derivative LYP3 to improve the water solubility and effectiveness. The inhibitory activity of LYP3 against APN was evaluated in vitro.

Previously, we reported that vitamin K3, which consists of a quinone component, inhibits the activity of human DNA polymerase γ (pol γ). In this study, we investigated the inhibitory effects of 4 quinone derivatives (1,4-benzoquinone (BQ), 1,4-naphthoquinone (NQ), 9,10-anthraquinone (AQ) and 5,12-naphthacenequinone (NCQ)) on the activity of mammalian pols. BQ and NQ potently inhibited the activity of all the pol species: pols α, β, γ, δ, ε and λ, and NQ was a stronger pol inhibitor than BQ. Because we previously found a positive relationship between pol λ inhibition and antiinflammatory action, we examined whether these quinone derivatives could inhibit inflammatory responses. BQ and NQ caused a marked reduction in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced acute inflammation in mouse ear, although AQ and NCQ did not. In a cell culture system using mouse macrophages, NQ displayed the strongest suppression in the production of tumor necrosis factor (TNF)-α induced by lipopolysaccharide (LPS) among the quinone derivatives tested. Moreover, NQ was found to inhibit the action of nuclear factor (NF)-κB. In an in vivo mouse model of LPSevoked acute inflammation, intraperitoneal injection of BQ and NQ to mice led to suppression of TNF-α production in serum. These anti-inflammatory responses of NQ were more potent than those of BQ. In conclusion, this study has identified several quinone derivatives, such as NQ, that are promising anti-inflammatory candidates.

A novel series of tetraethylene glycol (TEG) triazolyl and squaramide containing oxazolidinones were synthesized and tested for their antibacterial activity against a selected panel of Gram-positive and Gram-negative bacteria. The 4-TEG-triazolyl derivatives were prepared by ‘click reaction’. The introduction of the TEG and squaramide groups did not favor antibacterial activity. The three nucleoside-containing oxazolidinones were also prepared by ‘click’’ methodology resulted in weak antibacterial activity.

A series of ten compounds (Compounds J1-J10) of (±) 3-menthone aryl acid hydrazone was synthesized and characterized by thin layer chromatography and spectral analysis. Synthesized compounds were evaluated for anticonvulsant activity after intraperitoneal (i.p) administration to mice by maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure method and minimal clonic seizure test. Minimal motor impairment was also determined for these compounds. Results obtained showed that four compounds out of ten afforded significant protection in the minimal clonic seizure screen at 6 Hz. Compound J6, 4-Chloro-N-(2-isopropyl-5-methylcyclohexylidene) benzohydrazide was found to be the most active compound with MES ED50 of 16.1 mg/kg and protective index (pI) of greater than 20, indicating that (±) 3-menthone aryl acid hydrazone possesses better and safer anticonvulsant properties than other reported menthone derivatives viz. menthone Schiff bases, menthone semicarbazides and thiosemicarbazides.

Non-transferrin bound iron (NTBI) is found in plasma of β-thalassemia patients and causes oxidative tissue damage. Cardiac siderosis and complications are the secondary cause of death in β-thalassemia major patients. Desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX) are promising chelators used to get negative iron balance and improve life quality. DFP has been shown to remove myocardial iron effectively. Curcuminoids (CUR) can chelate plasma NTBI, inhibit lipid peroxidation and alleviate cardiac autonomic imbalance. Effects of CUR on cardiac iron deposition and function were investigated in iron-loaded mice. Wild type (muβ+/+; WT) and heterozygous β-knockout (muβth-3/+; BKO) mice (C57BL/6) were fed with ferrocene-supplemented diet (Fe diet) and coincidently intervened with CUR and DFP for 2 months. Concentrations of plasma NTBI and malondialdehyde (MDA) were measured using HPLC techniques. Heart iron concentration was determined based on atomic absorption spectrophotometry and Perl's staining methods. Short-term electrocardiogram (ECG) was recorded with AD Instruments Power Lab, and heart rate variability (HRV) was evaluated using MATLAB 7.0 program. Fe diet increased levels of NTBI and MDA in plasma, nonheme iron and iron deposit in heart tissue significantly, and depressed the HRV, which the levels were higher in the BKO mice than the WT mice. CUR and DFP treatments lowered plasma NTBI as well as MDA concentrations (p <0.05), heart iron accumulation effectively, and also improved the HRV in the treated mice. The results imply that CUR would be effective in decreasing plasma NTBI and myocardial iron, alleviating lipid peroxidation and improving cardiac function in iron-loaded thalassemic mice.

“The publishers have decided to retract the manuscript entitled “Synthesis and Pharmacological Activity of Potential Cocaine Antagonists. 2. Structure-Activity Relationship Studies of Piperidine Ring-Substituted Methylphenidate Analogs” published in Medicinal Chemistry (MC), volume 6, issue 4, page numbers 219-228, for the following reasons”. Starting points for the medicinal chemistry in the Dr. Ojo paper, as previously published by Prof. Deutsch, were not acknowledged by Dr. Ojo. There are no biological authors listed in the Dr. Ojo paper yet fundamental parts of the paper are, in fact, the binding and dopamine uptake results in Tables 2-3. In the biology experimental section, Dr. Ojo did not note where the results were generated (and merely noted that methodology was established in the Schweri lab). All these points constitute intellectual dishonesty and a form of Plagiarism.