Study of acute oral toxicity of organotin compounds containing a 2,6-di-tert-butylphenol fragment

The aim of the study was to evaluate the safety of the use of organotin compounds containing a fragment of 2,6-di-tert-butylphenol as pharmaceutical substances when administered intragastrically to Wistar outbred rats (females). Material and methods. The objects of the study were three organotin compounds: ((3,5-di-tertbutyl-4-hydroxyphenylthiolate) triphenyltin (Me-5), (3,5-di-tert-butyl-4-hydroxyphenylthiolate)trimethyltin (Me-4), bis(3,5-di-tert-butyl-4-hydroxyphenylthiolate) dimethyltin (Me-3). Acute toxicity study were performed on 106 Wistar rats (female) weighing 190-210 g by "fixed dose" and "up and down" methods according to the OECD protocols. Results. According to the harmonized system of hazard classification and labeling of chemical products (GHS) the studied organotin compounds should be assigned to the following toxicity classes: Me-5 — IV, Me-3 — V, Me-4 — II. Average lethal dose in intragastric administration for Me-5 is LD50 = 955.0 ± 58.3 mg/kg, the value of LD50 for Me-3 is conventionally assumed to be much more than 2000 mg/kg, for Me-4 is in the range of 5 to 50 mg/kg. Discussion. The modification of tin-organic molecules in the course of directed synthesis opens broad prospects for the creation of a new class of anticancer drugs. In the course of the experimental study, the regularities of the "structure-toxicity" relationship of organic tin derivatives were revealed: the introduction of the 2,6-di-tert-butylphenol group significantly reduces toxicity compared to the corresponding initial substances; methyl derivatives are more toxic than their phenyl analogues. Compounds of GHS toxicity classes IV and V can be considered as leading candidates for promising preclinical studies in the field of experimental oncology. Conclusion. Substances of Me-3 and Me-5, which have the highest safety for intragastric use, were recommended for further study as antitumor drug agents.

Marine paralytic shellfish toxins: chemical properties, mode of action, newer analogues, and structure–toxicity relationship

This review highlights the recent findings about biotransformation in different organisms (dinoflagellates, bivalves, humans) and presents a critical revision on the latest analogues, M-toxins. A “toxicological traffic light” is also proposed.

HUBUNGAN KUANTITATIF STRUKTUR TOKSISITAS : REVIEW

AbstrakProses penemuan dan pengembangan obat merupakan proses panjang yang memerlukan banyak waktu dan biaya. Ada banyak calon molekul obat yang gagal mencapai pasaran karena alasan toksisitasnya yang tinggi, sehingga harus dapat diidentifikasi sedini mungkin. Hubungan kuantitatif struktur toksisitas (HKST) merupakan salah satu metode in silico yang cukup tangguh untuk memprediksi toksisitas. HKST merupakan persamaan matematis yang dibentuk dari variabel data endpoint toksisitas seperti LD50 sebagai variabel terikat dan sejumlah deskriptor sebagai variable bebas yang dihitung dari senyawa-senyawa dalam training set. Persamaan HKST kemudian digunakan untuk memprediksi toksisitas senyawa baru.Kata kunci : toksisitas, hubungan kuantitatif struktur toksisitas (HKST)AbstractThe process of drug discovery and development is a long process that requires a lot of time and costly. There are many prospective drug molecules that fail to reach the market due to high toxicity reasons, so they must be identified as early as possible. The quantitative structure toxicity relationship (QSTR) is one of the in silico methods that is strong enough to predict toxicity. QSTR is a mathematical equation formed from endpoint toxicity data variables such as LD50 as a bound variable and a number of descriptors as independent variables calculated from the compounds in the training set. The QSTR equation is then used to predict the toxicity of new compounds.Keywords: toxicity, quantitative structure toxicity relationship (QSTR)

Rationally Designed Antibodies as Research Tools to Study the Structure–Toxicity Relationship of Amyloid-β Oligomers

Alzheimer’s disease is associated with the aggregation of the amyloid-β peptide (Aβ), resulting in the deposition of amyloid plaques in brain tissue. Recent scrutiny of the mechanisms by which Aβ aggregates induce neuronal dysfunction has highlighted the importance of the Aβ oligomers of this protein fragment. Because of the transient and heterogeneous nature of these oligomers, however, it has been challenging to investigate the detailed mechanisms by which these species exert cytotoxicity. To address this problem, we demonstrate here the use of rationally designed single-domain antibodies (DesAbs) to characterize the structure–toxicity relationship of Aβ oligomers. For this purpose, we use Zn2+-stabilized oligomers of the 40-residue form of Aβ (Aβ40) as models of brain Aβ oligomers and two single-domain antibodies (DesAb18-24 and DesAb34-40), designed to bind to epitopes at residues 18–24 and 34–40 of Aβ40, respectively. We found that the DesAbs induce a change in structure of the Zn2+-stabilized Aβ40 oligomers, generating a simultaneous increase in their size and solvent-exposed hydrophobicity. We then observed that these increments in both the size and hydrophobicity of the oligomers neutralize each other in terms of their effects on cytotoxicity, as predicted by a recently proposed general structure–toxicity relationship, and observed experimentally. These results illustrate the use of the DesAbs as research tools to investigate the biophysical and cytotoxicity properties of Aβ oligomers.

QSTR Analysis of Acute Rat Oral Toxicity of Amide Pesticides

The rodent acute toxicity is gaining much attention in the ecotoxicological assessment of chemicals. Among the available amide pesticides, the majority of compounds are lacking the experimental toxicity values of rat oral toxicity. In order to explore the structural alerts for toxicity and to fill the toxicity data gap through in silico studies, a series of statistically robust local quantitative structure-toxicity relationship (QSTR) models were developed for the prediction of acute oral toxicity of amide pesticides on rat following OECD principles. The mechanistic interpretation indicated types of amide, the presence of halogen, and SO2 functionality were influential for the toxicity. Applicability domain (AD) analysis and prediction reliability indicators assured the robustness and reliability of the developed models. The detailed analyses of the AD as well the consensus predictions of the unknown compounds were commented for their toxic nature, and prioritization was done for similar classes of compounds without experimental values.