Π‘ΠΈΠ½Ρ‚Π΅Π·Π° Π½ΠΎΠ²ΠΈΡ… биолошки Π°ΠΊΡ‚ΠΈΠ²Π½ΠΈΡ… ΠΊΠΎΠ½Ρ˜ΡƒΠ³Π°Ρ‚Π° стСроида са Ρ„Π΅Ρ€ΠΎΡ†Π΅Π½ΠΎΠΌ ΠΈ ΠΈΠ΄Π΅Π½Ρ‚ΠΈΡ„ΠΈΠΊΠ°Ρ†ΠΈΡ˜Π° Π½ΠΎΠ²ΠΈΡ… ΠΏΡ€ΠΈΡ€ΠΎΠ΄Π½ΠΈΡ… ΠΏΡ€ΠΎΠΈΠ·Π²ΠΎΠ΄Π° ΠΈΠ· Ρ†Ρ€Π½Π΅ Π·ΠΎΠ²Π΅ (Sambucus nigra L.) - PhDData

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Π‘ΠΈΠ½Ρ‚Π΅Π·Π° Π½ΠΎΠ²ΠΈΡ… биолошки Π°ΠΊΡ‚ΠΈΠ²Π½ΠΈΡ… ΠΊΠΎΠ½Ρ˜ΡƒΠ³Π°Ρ‚Π° стСроида са Ρ„Π΅Ρ€ΠΎΡ†Π΅Π½ΠΎΠΌ ΠΈ ΠΈΠ΄Π΅Π½Ρ‚ΠΈΡ„ΠΈΠΊΠ°Ρ†ΠΈΡ˜Π° Π½ΠΎΠ²ΠΈΡ… ΠΏΡ€ΠΈΡ€ΠΎΠ΄Π½ΠΈΡ… ΠΏΡ€ΠΎΠΈΠ·Π²ΠΎΠ΄Π° ΠΈΠ· Ρ†Ρ€Π½Π΅ Π·ΠΎΠ²Π΅ (Sambucus nigra L.)

The thesis was published by RaičeviΔ‡ Vidak, in September 2023, University of Novi Sad.

Abstract:

Steroid–ferrocene conjugates are a class of compounds of interest in medicinal chemistry due to their diverse range of biological activities. This doctoral thesis focused on the synthesis of new conjugates of estra-1,3,5(10)-trienes (2–6, 8– 10), androstanes (11–15) and pregnanes (16–23), while selected compounds were tested in vitro to evaluate their antiproliferative and immunomodulatory effects. In the case of derivatives furnished by alkylating estradiol and estrone by (ferrocenylmethyl)trimethylammonium iodide (2–6), compound 3 stood out, as it was found to exhibit a significantly low IC50 value of 0.34 ΞΌM toward a hormone-dependent breast cancer cell line (MCF-7), which rendered this compound the most antiproliferative steroid–ferrocene conjugate known to date. Compound 8, obtained by condensing 2-formylestradiol and acetylferrocene, was discovered to be unstable to such an extent that it was impossible to isolate it in pure form, while its monoacetate (9) and diacetate (10) could be isolated. It was concluded that the condensation of testosterone and ferrocenecarbaldexyde furnishes two geometric isomers 11 and 12, while the condensation of dihydrotestosterone and this aldehyde gives the E configured conjugate 13 as the sole product; the catalytic hydrogenation of this compound produced the C-3 deoxygenated compound 14 and the 2Ξ±- (ferrocenylmethyl) derivative 15. Compounds 11–15 demonstrated ntiproliferative activity against hormone-independent (PC-3) and hormone dependent (LNCaP) prostate cancer cell lines in a micromolar range of IC50 values, but similar activities were also detected against normal fetal lung fibroblasts (MRC-5), a noncancerous cell line, possibly relating this type of activity to a seemingly low affinity of these compounds for the androgen receptor. Conjugates of ferrocene with pregnane-series steroids 16–23 were obtained through condensation reactions involving five different pregnane-20- ones, and each of these compounds was found to inhibit the proliferation of splenocytes stimulated by bacterial lypopolysaccharide. Furthermore, a total of 252 compounds were identified in the essential oil of dry elder (Sambucus nigra L.) flowers using gas chromatography, along with isolation and synthesis procedures, and coinjection experiments. Among these compounds, seven (24– 30) were identified as new natural products. An abundance of (Z)-hex-3-en-1-ol and its esters was noticed in the oil, along with at least three esters of isosenecioic acid. The imine of the isoleucine methyl ester with benzaldehyde (31) was found in elder for the first time, as well as a homologue series of imines of this ester with aliphatic n-aldehydes (32–44), which were detected in ethereal washings of fresh flowers. A full spin analysis of 1H NMR spectra of trans hotrienol and trans-hodiendiol was performed. A case of an ongoing misidentification of 2-methyl-2-en-4-one in various plant species was uncovered, as 5-oxolinalool was mistaken for this compound due to similar mass spectra and an erroneous literature statement regarding the retention index of this compound.



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