12 research outputs found
Synthesis and antiproliferative activity of some A- and B modified D-homo lactone androstane derivatives
An efficient synthesis of several A- and B-modified D-homo lactone androstane
derivatives from 3β-hydroxy-17-oxa-D-homoandrost-5-en-16-one (1) is reported.
17-Oxa-Dhomoandrost- 4-ene-3,16-dione (2), obtained by the Oppenauer
oxidation of compound 1, was converted via the unstable intermediate
3,16-dioxo-4,17-dioxa-D-homoandrostane- 5α-carboxaldehyde (3) to
17-oxa-D-homo-3,5-seco-4-norandrostan-5-one-3-carboxylic acid (4), which was
also obtained directly from compound 2. Compound 1 was acetylated to give
17-oxa-D-homoandrost-5-en-16-on-3β-yl acetate (5) which was then oxidized
with chromium(VI)-oxide in 50% acetic acid or with meta-chlorperbenzoic acid
and chromium(VI)-oxide to yield compounds 6-8 and
5α-hydroxy-17-oxa-D-homoandrostane- 6,16-dion-3β-yl acetate (9),
respectively. The oximination of compound 9 gave a mixture of
6(E)-hydroximino-5α-hydroxy-17-oxa-D-homoandrostan-16-on-3β-yl acetate (10)
and 6(Z)-hydroximino-5α-hydroxy-17-oxa-D-homoandrostan-16-on-3β-yl acetate
(11), the hydrolysis of which gave
6(E)-hydroximino-3β,5α-dihydroxy-17-oxa-D-homoandrostan- 16-one (12) and
6(Z)-hydroximino-3β,5α-dihydroxy-17-oxa-D-homoandrostan-16-one (13).
6-Nitrile-17-oxa-5,6-seco-D-homoandrostane-5,16-dion-3β-yl acetate (14) was
obtained under the Beckmann fragmentation of compounds 10 and 11. Only pure
and stable compounds (1, 2, 4, 5, 9 and 14) were tested in vitro on six
malignant cell lines (MCF-7, MDA-MB-231, PC-3, HeLa, HT-29, K562) and one
non-tumor MRC-5 cell line. Significant antiproliferative activity against
MDA-MB-231 cells showed compounds 1, 5 and 9, while compound 2 exhibited a
strong antiproliferative activity. Only compound 14 showed weak
antiproliferative activity against MCF-7 cells. All tested compounds were not
toxic on MRC-5 cells, whereas Doxorubicin was highly toxic on these cells.
[Projekat Ministarstva nauke Republike Srbije, br. 172021
SCIENTIFIC WORK SYNTHESIS OF SOME 16,17-SECO- ANDROST-5-ENE DERIVATIVES
16,17-secoandrost-5-ene-16-nitrile (4) was synthesized by a three-stage procedure. First, the formyl group of compound 1 was reduced, to yield the alcohol 2. Compound 2 was further transformed to the mesyloxy derivative 3, whose reduction with NaBH 3CN gave compound 4. Apart from compound 4 as the main reaction product, two additional products were obtained, for which the GC/MS analysis suggested that they are Δ 8(14) and Δ 14 derivatives of compound 4. Compound 4 was transformed into 3β-hydroxy-16,17-secoandrost-5-ene-16-nitrile (7), the Oppenauer oxidation of which afforded 3-oxo-16,17-secoandrost-4-ene-16-nitrile (8). UDC 547.92.057:615.2 DOI: 10.2298/HEMIND100212009G There are various ways of reducing the C=O group of aldehydes and ketones to a CH2 [1]. The two oldest methods are the Wolff–Kishner reduction and the Clemensen reduction. In the Wolff–Kishner reduction, the aldehyde or ketone is heated with hydrazine hydrate an
Synthesis of some D-homo-D-aza estratriene derivatives
In this paper two synthetic routes for obtaining D-homo-D-aza estratriene derivatives were described. Namely, starting from 3-methoxyestra-1,3,5(10)-trien-16-oximino-17-one (1) 3-methoxy-17-aza-D-homoestra-1,3,5(10)-triene (5) was synthesized in two step. Another D-aza derivative was synthesize, starting from 3-methoxy-17-oxo-16,17-secoestra-1,3,5(10)-trien-16-nitrile (6). For that purpose, the seco-cyanoaldehyde was converted into its 17-ethylenacetal 7 followed by subsequent reduction of the nitrile function with sodium borohydride in the presence of cobalt chloride hexahydrate. Finally, under acidic conditions the obtained 16-amino-17-ethylenacetal 8 was transformed into 3-metoxy-17-aza-D-homoestra-1,3,5(10),17(17a)-tetraene (9)
Synthesis and cytotoxic activity of a series of bile acid derivatives
The new conjugates of selected bile acids (hyocholic (2), deoxycholic (3), hyodeoxycholic (4) and 12-ketocholic (5) acids) with ethyl 11-aminoundecanoate 7, 8, 11, and 13 were synthesized. The conjugation reaction was carried out in ethyl acetate in the presence of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) and triethylamine. Under the same experimental conditions, the conjugation reaction involving ethyl 6-aminohexanoate resulted in formation of a conjugate 9 only in the case of deoxycholic acid (3) in addition to the unexpected ethyl ester 10. In the case of the other bile acids (cholic (1), hyodeoxycholic (4) and 12-ketocholic (5) acids) only an unexpected ester formation took place giving esters 6, 12, and 14. Cytotoxic activity against four tumor cell lines (human breast adenocarcinoma ER-, MDA-MB-231; breast adenocarcinoma ER+, MCF-7; cervix epiteloid carcinoma, HeLa S-3; and prostate cancer, PC-3) was evaluated. Conjugate 8 showed strong activity against HeLa S-3 and conjugate 11 for PC-3. Ethyl ester of 12-ketocholic acid 14 showed very strong antiproliferative activity against MCF-7 and HeLa S-3
SYNTHESIS AND CYTOTOXIC ACTIVITY OF A SERIES OF BILE ACID DERIVATIVES
The new conjugates of selected bile acids (hyocholic (2), deoxycholic (3), hyodeoxycholic (4) and 12-ketocholic (5) acids) with ethyl 11-aminoundecanoate 7, 8, 11, and 13 were synthesized. The conjugation reaction was carried out in ethyl acetate in the presence of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) and triethylamine. Under the same experimental conditions, the conjugation reaction involving ethyl 6-aminohexanoate resulted in formation of a conjugate 9 only in the case of deoxycholic acid (3) in addition to the unexpected ethyl ester 10. In the case of the other bile acids (cholic (1), hyodeoxycholic (4) and 12-ketocholic (5) acids) only an unexpected ester formation took place giving esters 6, 12, and 14. Cytotoxic activity against four tumor cell lines (human breast adenocarcinoma ER-, MDA-MB-231; breast adenocarcinoma ER+, MCF-7; cervix epiteloid carcinoma, HeLa S-3; and prostate cancer, PC-3) was evaluated. Conjugate 8 showed strong activity against HeLa S-3 and conjugate 11 for PC-3. Ethyl ester of 12-ketocholic acid 14 showed very strong antiproliferative activity against MCF-7 and HeLa S-3. Studies of bile acids, their physiology and metabolism
Antioxidant and cytotoxic activity of mono- and bissalicylic acid derivatives
A simple synthesis of mono- and bis-salicylic acid derivatives 1-10 by the
transesterification of methyl salicylate (methyl 2-hydroxybenzoate) with
3-oxapentane-1,5-diol, 3,6- dioxaoctane-1,8-diol,
3,6,9-trioxaundecane-1,11-diol, propane-1,2-diol or 1-aminopropan- 2-ol in
alkaline conditions is reported. All compounds were tested in vitro on three
malignant cell lines (MCF-7, MDA-MB-231, PC-3) and one non-tumor cell line
(MRC- 5). Strong cytotoxicity against prostate PC-3 cancer cells expressed
compounds 3, 4, 6, 9 and 10, all with the IC50 less than 10 μmol/L, which
were 11-27 times higher than the cytotoxicity of antitumor drug doxorubicin.
All tested compounds were not toxic against the non-tumor MRC-5 cell line.
Antioxidant activity of the synthesized derivatives was also evaluated.
Compounds 2, 5 and 8 were better OH radical scavengers than commercial
antioxidants BHT and BHA. The synthesized compounds showed satisfactory
scavenger activity, which was studied by QSAR modeling. A good correlation
between the experimental variables IC50 DPPH and IC50 OH and MTI (molecular
topological indices) molecular descriptors and CAA (accessible Connolly
solvent surface area) for the new compounds 1, 3, and 5 was observed
X-ray structural analysis, antioxidant and cytotoxic activity of newly synthesized salicylic acid derivatives
New salicylic (2-hydroxybenzoic) acid derivatives 1–6 were prepared by conventional heating or microwave irradiation of a mixture consisting of methyl salicylate and the corresponding amino alcohol (2,2'-dihydroxydiethylamine, 2,2',2?-trihydroxytriethylamine or N-phenyl-2,2'-dihydroxydiethylamine) and metallic sodium as catalyst. For compounds 1, 3, and 5 X-ray structure analysis was performed, as well as molecular mechanics calculations (MMC), to define their conformation in terms of their energy minima. Comparison of crystal and MMC structures for these three compounds (1, 3, and 5) revealed that the intramolecular hydrogen bonds play an important role, stabilizing conformation of the most part of the molecule. The antioxidant activity and cytotoxicity of the synthesized derivatives were evaluated in a series of in vitro tests. The newly synthesized compounds exhibited strong activity against hydroxyl radical, as well as promising lipid peroxidation inhibition. The study showed that the electronic effects of the groups at the N atom are responsible for neutralization of the OH radical, i.e., antioxidant activity. Compounds 1–3 exhibited sub-micromolar cytotoxicity against HeLa S3, whereas compounds 1, 3 and 5 efficiently inhibited the growth of PC3 cells