Inhibition of thymocyte RNA synthesis by natural adrenal steroids and their 1,4-diene analogs. Structure-activity correlations using 13C-n.m.r. spectroscopy
| Autor: | Gerardo Burton, M. B. Castillo, María C. Damasco, C.P. Lantos, A. Roldán |
|---|---|
| Rok vydání: | 1981 |
| Předmět: |
Male
Steric effects Magnetic Resonance Spectroscopy Lysis Double bond Diene Stereochemistry medicine.medical_treatment Thymus Gland In Vitro Techniques Biochemistry Steroid Structure-Activity Relationship chemistry.chemical_compound Endocrinology Corticosterone medicine Animals Glucocorticoids Uridine chemistry.chemical_classification Chemistry Rats Inbred Strains Resonance (chemistry) Rats Thymocyte RNA Female |
| Zdroj: | Journal of Steroid Biochemistry. 15:467-472 |
| ISSN: | 0022-4731 |
| DOI: | 10.1016/0022-4731(81)90316-2 |
| Popis: | Inhibitory properties—as indicated in the title—of natural adrenal steroids are correlated to typical functional groups and to certain preferred conformations, the latter studied by 13C-n.m.r. spectroscopy. 11β-hydroxyprogesterone (HOP), corticosterone (B), cortisol (F) and deoxycorticosterone (DOC) were compared to their 1,4-diene analogs pregna-1,4-diene-11β-ol-3,20-dione (ΔHOP). pregna-1,4-diene-11β,21-diol-3,20-dione (ΔB). pregna-1,4-diene-11β,17α,21-triol-3,20-dione (ΔF) and pregna-1,4-diene-21-ol-3.20-dione (ΔDOC) as to their ability to inhibit the uptake of [3H]-uridine by thymocytes of adrenalectomized rats. When the 21-hydroxy group is absent, the introduction of a 1,2 double bond (HOP/ΔHOP) produces a marked increase in inhibitory activity at very high steroid concentration (10−4 M) but no additional effect in this activity at low concentrations (10−8–10−6 M). The presence of the 21-hydroxy—in the absence of the 17-hydroxy group—in contrast, makes the 1,4-diene analog not to differ substantially from the 4-ene compound (B/ΔB or DOC/ΔDOC) over the concentration range studied (10−8–10−4M). At 10−8M ΔF was significantly more active than F; at higher concentrations dispersions between experiments of the responses to ΔF were too high to evidence any differences. Differences observed in cell lysis between experiments can be probably—but not entirely—hold responsible for the aforementioned high dispersions. 13C-n.m.r. spectroscopy reveals that, upon introduction of a 1,2-ene double bond, the 11β-hydroxy elicited downfield shift of the C-19 methyl resonance decreases; this decrease varies from steroid to steroid suggesting a correlative bending of the A ring towards the α face. On the other hand the downfield shift of the C-18 methyl resonance decreases only for ΔHOP, probably due to other steric interactions between this angular methyl and the hydroxy groups in position 21 and/or 17 of ΔB and ΔF. Hence the present inhibitory effect (but not necessarily cell lysis) is increased in 11β-hydroxy-pregnane steroids: (a) By the C-21 hydroxyl at low (10−8 to 10−6 M), but not at higher (10−4 M) steroid concentrations. 1. (b) By conformational changes only at very high steroid concentration (10−4 M) in the absence of a 21-hydroxy group or at very low concentrations (10−8 M) in the presence of both 17α- and 21-hydroxy groups. Two coexisting mechanisms are postulated, one depending on the conformation of the steroid molecule and the other one on functional groups. |
| Databáze: | OpenAIRE |
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