Evaluation of molecular descriptors for antitumor drugs with respect to noncovalent binding to DNA and antiproliferative activity

34 pages, 6 additional files, 5 tables, 4 figures.[Background ] Small molecules that bind reversibly to DNA are among the antitumor drugs currently used in chemotherapy. In the pursuit of a more rational approach to cancer chemotherapy based upon these molecules, it is necessary to exploit the interdependency between DNA-binding affinity, sequence selectivity and cytotoxicity. For drugs binding noncovalently to DNA, it is worth exploring whether molecular descriptors, such as their molecular weight or the number of potential hydrogen acceptors/donors, can account for their DNA-binding affinity and cytotoxicity.[Results] Fifteen antitumor agents, which are in clinical use or being evaluated as part of the National Cancer Institute’s drug screening effort, were analyzed in silico to assess the contribution of various molecular descriptors to their DNA-binding affinity, and the capacity of the descriptors and DNA-binding constants for predicting cell cytotoxicity. Equations to predict drug-DNA binding constants and growth-inhibitory concentrations were obtained by multiple regression following rigorous statistical procedures.[Conclusions] For drugs binding reversibly to DNA, both their strength of binding and their cytoxicity are fairly predicted from molecular descriptors by using multiple regression methods. The equations derived may be useful for rational drug design. The results obtained agree with that compounds more active across the National Cancer Institute’s 60-cell line data set tend to have common structural features.Supported by a grant from the former Spanish Ministry of Education and Science (BFU2007-60998) and the FEDER program of the European Community.Peer reviewe

An Analysis for Adulteration and Contamination of Over-the-Counter Weight-Loss Products.

Six Australian and five overseas complementary medicines (CM) and meal replacement shake products were analysed for potential adulteration with two common active pharmaceutical ingredients, caffeine and sibutramine, using thin-layer chromatography and mass spectrometry. The declared amount of caffeine in each product was also reviewed. Finally, the products were examined for heavy metal contamination using inductively coupled plasma-mass spectrometry. The results showed that there was no detected adulteration of either caffeine (for those products that did not list caffeine as an ingredient) or sibutramine in the 11 products; however, based on the product labels, one Australian and one overseas (two in total) CM product contained more than the maximum daily safety limit (400 mg) of caffeine. Potentially excessive lead and/or chromium was detected in six products, including four Australian products and two products purchased online. One Australian CM product appeared to contain these heavy metals at concentrations at, or exceeding, the safety limits specified in the United States Pharmacopeia or set by the World Health Organization. The overconsumption of caffeine and heavy metals has the potential of causing significant health effects in consumers

Analysis of montmorillonite clay as a vehicle in platinum anticancer drug delivery

As a proof-of-concept study, the platinum anticancer complex [(1,10-phenanthroline)(1S,2S-diaminocyclohexane)platinum(II)]chloride, PHENSS, was loaded into montmorillonite (MMT) clay to evaluate its utility as a drug delivery vehicle. Loading is complete within one hour and the total amount of PHENSS that can be loaded into the clay is based on the PHENSS solution concentration in which the MMT is suspended. From a PHENSS solution concentration of 30 mM, a maximum loading of 0.257 mmol per gram of MMT can be achieved. The pH of the solution also has an effect with a solution pH of 6 giving maximum loading of PHENSS. Metal complex release from the MMT was examined using the dialysis bag and dispersion methods. PHENSS is incompletely released from MMT; after 4 h just 47% has been released from the clay using the dialysis method and 30% using the dispersion method. The release is also very fast with a half-life of just 10-16 min. The MMT was shown to have a negative effect on the in vitro cytotoxicity of PHENSS in the human breast cancer cell lines MCF-7 and MDA-MB-231, presumably due to the incomplete release of the metal complex from the clay. Overall the results demonstrate that MMT is not a suitable slow release vehicle for PHENSS, although it may still be of use to other platinum complexes and drugs. © 2014 Elsevier B.V. All rights reserved

para-Sulfonatocalix[4]arene and polyamidoamine dendrimer nanocomplexes as delivery vehicles for a novel platinum anticancer agent

© 2017 Novel para-sulfonatocalix[4]arene (sCX[4]) and polyamidoamine (PAMAM) dendrimer nanocomplexes were evaluated as delivery vehicles for the platinum anticancer agent [(1,10-phenanthroline)(1S,2S-diaminocyclohexane)platinum(II)] chloride (PHENSS). Different ratios of sCX[4] to PHENSS were tested for their compatibility, with a ratio of 6:1 sCX[4]:PHENSS having the best solubility. The loading of sCX[4], and sCX[4]-bound PHENSS, onto three different generations of PAMAM dendrimers (G3.0–5.0) was examined using UV–visible spectrophotometry. The quantity of sCX[4] bound was found to increase exponentially with dendrimer size: G3, 15 sCX[4] molecules per dendrimer; G4, 37; and G5, 78. Similarly, the loading of sCX[4]-bound PHENSS also increased with increasing dendrimer size: G3, 7 PHENSS molecules per dendrimer; G4, 14; and G5, 28.5. The loading of sCX[4]-bound PHENSS molecules is significantly lower when compared with that of sCX[4], which indicates that less than half of the binding sites were occupied (45, 44, and 44%, respectively). By 1H NMR and UV–vis analysis, the nanocomplex was found to be stable in NaCl solutions at concentrations up to 150 mM. While PHENSS is more active in vitro than cisplatin against the human breast cancer cell line, MCF-7, delivery of PHENSS using the sCX[4]-dendrimer nanocomplexes, regardless of dendrimer generation, had little effect on PHENSS cytotoxicity. The results of this study may have application in the delivery of a variety of small molecule metal-based drugs for which chemical conjugation to a nanoparticle is undesired or not feasible

An evaluation of garlic products available in Australian pharmacies–From the label to the laboratory

Garlic is one of the most commonly used herbal medicines worldwide. There is medium quality evidence to support that specific garlic formulations at specific doses have an antihypertensive effect in a cohort of individuals with hypertension. There is lower quality evidence for garlic’s hypolipidaemic effects. While there are many garlic products available in Australian pharmacies, it is unclear if these products are formulated based on the current evidence for use in such populations. The aim of this study was to evaluate garlic product formulations available in Australian pharmacies for quality indicators including: supporting evidence, labelling, product, safety and manufacturing information and the presence of key constituents previously identified as having hypotensive or hypolipidaemic properties. A qualitative evaluation of commercially available garlic products was conducted in accordance with the study aims. Thin-layer chromatography (TLC) was included in the evaluation to investigate the presence of alliin and s-allyl cysteine in both garlic products and raw garlic. The quality indicators evaluated in this study including evidence for the formulation used, labelling, product, safety and manufacturing information and key constituents varied significantly between the garlic products available in Australian pharmacies. These findings have a number of implications that relate to the formulations and doses chosen by herbalists, pharmacists and consumers who may consider using garlic products in the management of hypertension and/or dyslipidaemia

Host-Guest Complexes of Carboxylated Pillar[n]arenes With Drugs.

Pillar[n]arenes are a new family of nanocapsules that have shown application in a number of areas, but because of their poor water solubility their biomedical applications are limited. Recently, a method of synthesizing water-soluble pillar[n]arenes was developed. In this study, carboxylated pillar[n]arenes (WP[n], n = 6 or 7) have been examined for their ability to form host-guest complexes with compounds relevant to drug delivery and biodiagnostic applications. Both pillar[n]arenes form host-guest complexes with memantine, chlorhexidine hydrochloride, and proflavine by 1H nuclear magnetic resonance and modeling. Binding is stabilized by hydrophobic effects within the cavities, and hydrogen bonding and electrostatic interactions at the portals. Encapsulation within WP[6] results in the complete and efficient quenching of proflavine fluorescence, giving rise to "on" and "off" states that have potential in biodiagnostics. The toxicity of the pillar[n]arenes was examined using in vitro growth assays with the OVCAR-3 and HEK293 cell lines. The pillar[n]arenes are relatively nontoxic to cells except at high doses and after prolonged continuous exposure. Overall, the results show that there could be a potentially large range of medical applications for carboxylated pillar[n]arene nanocapsules