Osteolathyrogenic effects and structure-activity analysis for a series of acid hydrazines

Author

Geoffrey W. Riggin

Date of Award

6-1985

Degree Type

Thesis

Degree Name

Master of Science

Major

Life Sciences

Major Professor

Terry W. Schultz

Committee Members

John R. Kennedy

Abstract

The osteolathyrogenic effects and structure-activity relationships (SAR) of a homologous series of hydrazines were examined using the Frog Embryo Teratogenesis Assay; Xenopus (FETAX). Osteolathyrism is a connective tissue disease associated with decreased intermolecular bonding of collagen fibers. SAR is utilized in the association of a specific biological effect with chemical structure. By analyzing the chemical and physical properties of a compound and relating the biological effects manifested, predictive models can be generated, which may then be applied to predict the effects of other compounds. FETAX is a rapid and inexpensive in vitro bioassay for teratogenesis, which has several easily observed end-points including mortality, abnormality, growth, developmental stage, and microscopic anatomy.

The 96-hr EC₅₀ (concentration producing abnormals in 50% of survivors) and LC ₅₀ (concentration causing lethalities in 50% of embryos) were determined at both 20°C and 25°C for each compound. These were found to be concentration, and to a lesser extent developmental stage dependent. From these values a teratogenic index (TI) was calculated. The TI is a basis for comparing the relative risk of teratogenic agents.

Morphological examination was done 1) grossly, with 2) light microscopy, and 3) electron microscopy. Osteolathyrism induced in the frog embryo is manifested primarily as alterations in the notochord. The lathyrogenic effects of these hydrazines were shown to be produced by extracellular influences on the cross-linking of collagen fibrils.

The activity of each compound varied with changes in both size and number of organic side groups. These variations are due to the partitioning and/or steric hinderance (bulkiness) characteristics of each substitution. A strong inverse relationship was found between the TI of the mono-substituted compounds and the molecular descriptors, MR (molar refractivity) and ¹Χ^V(one-chi-V, molecular connectivity index).

Recommended Citation

Riggin, Geoffrey W., "Osteolathyrogenic effects and structure-activity analysis for a series of acid hydrazines. " Master's Thesis, University of Tennessee, 1985.
https://trace.tennessee.edu/utk_gradthes/14430