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Synthesis, characterization and biological evaluation of some novel P-heterocyclic androst-4-ene derivatives

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2013
Authors
Krstić, Natalija
Pavlović, Vladimir D.
Novaković, Irena
Matić, Ivana Z.
Sladić, Dušan
Article (Published version)
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Abstract
The reactions of 21-hydroxyprogesterone with Lawesson's reagent in toluene or gave four P-heterocyclic androst-4-ene derivatives (two tautomeric pairs): 4-(3-thioxoandrost-4-en-17-yl)-1,3,2-oxathiaphosphole-2- sulfide (2), 4-(3-thioxoandrost-4-en-17-ylidene)-1,3,2-oxathiaphospholane-2-sulfide (3), 4-(3-oxoandrost-4-en-17-yl)-1,3,2-oxathiaphosphole-2-sulfide (4), and 4-(3-oxoandrost-4-en-17-ylidene)-1,3,2- oxathiaphospholane-2-sulfide (5). The structures of all novel 17-substituted steroids were elucidated from their analytic and spectral data (HRMS, IR, 1D NMR and 2D NMR-HSQC, HMBC, NOESY, COSY). The detailed NMR analysis for all compounds revealed the presence of two pairs of signals in approx. 8:2 ratio indicating the existence of two diastereoisomers (a and b) with different configurations at the phosphorus atom. A parallel analysis of heteronuclear 2D - spectra (HSQC and HMBC) and homonuclear 2D spectra (NOESY and COSY) enabled complete and assignments of each isomer and provided e...vidence for the preferred configuration on phosphorus atom. Cytotoxic activity in vitro was tested against four tumor cell lines (human cervix carcinoma HeLa cells, chronic myelogenous leukemia K-562 and two human breast carcinoma MDA-MB-361 and MDA-MB-453 cells). Compounds 3a,b and 4a,b showed a poor activity against HeLa and MDA-MB-453 cell lines, while against MDA-MB-361 cell line, all tested compounds exerted very weak cytotoxic effect. All compounds exerted moderate activity against K562 cells. Antimicrobial activity against Gram-positive, Gram-negative bacteria and fungal cells, and toxicity to brine shrimp Artemia salina were evaluated. All tested compounds showed strong antifungal activity.

Keywords:
21-Hydroxyprogesterone / Lawesson's reagent / 17-Substituted androstene derivatives / Phosphorus heterocycle / cytotoxic activity / Antimicrobial activity
Source:
Molecular Diversity, 2013, 17, 3, 547-561
Publisher:
  • Springer, Dordrecht
Funding / projects:
  • Interactions of natural products, their derivatives and coordination compounds with proteins and nucleic acids (RS-172055)

DOI: 10.1007/s11030-013-9455-9

ISSN: 1381-1991

PubMed: 23748368

WoS: 000321912600013

Scopus: 2-s2.0-84880794449
[ Google Scholar ]
8
7
URI
https://cer.ihtm.bg.ac.rs/handle/123456789/1200
Collections
  • Radovi istraživača / Researchers' publications
Institution/Community
IHTM
TY  - JOUR
AU  - Krstić, Natalija
AU  - Pavlović, Vladimir D.
AU  - Novaković, Irena
AU  - Matić, Ivana Z.
AU  - Sladić, Dušan
PY  - 2013
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/1200
AB  - The reactions of 21-hydroxyprogesterone with Lawesson's reagent in toluene or gave four P-heterocyclic androst-4-ene derivatives (two tautomeric pairs): 4-(3-thioxoandrost-4-en-17-yl)-1,3,2-oxathiaphosphole-2- sulfide (2), 4-(3-thioxoandrost-4-en-17-ylidene)-1,3,2-oxathiaphospholane-2-sulfide (3), 4-(3-oxoandrost-4-en-17-yl)-1,3,2-oxathiaphosphole-2-sulfide (4), and 4-(3-oxoandrost-4-en-17-ylidene)-1,3,2- oxathiaphospholane-2-sulfide (5). The structures of all novel 17-substituted steroids were elucidated from their analytic and spectral data (HRMS, IR, 1D NMR and 2D NMR-HSQC, HMBC, NOESY, COSY). The detailed NMR analysis for all compounds revealed the presence of two pairs of signals in approx. 8:2 ratio indicating the existence of two diastereoisomers (a and b) with different configurations at the phosphorus atom. A parallel analysis of heteronuclear 2D - spectra (HSQC and HMBC) and homonuclear 2D spectra (NOESY and COSY) enabled complete and assignments of each isomer and provided evidence for the preferred configuration on phosphorus atom. Cytotoxic activity in vitro was tested against four tumor cell lines (human cervix carcinoma HeLa cells, chronic myelogenous leukemia K-562 and two human breast carcinoma MDA-MB-361 and MDA-MB-453 cells). Compounds 3a,b and 4a,b showed a poor activity against HeLa and MDA-MB-453 cell lines, while against MDA-MB-361 cell line, all tested compounds exerted very weak cytotoxic effect. All compounds exerted moderate activity against K562 cells. Antimicrobial activity against Gram-positive, Gram-negative bacteria and fungal cells, and toxicity to brine shrimp Artemia salina were evaluated. All tested compounds showed strong antifungal activity.
PB  - Springer, Dordrecht
T2  - Molecular Diversity
T1  - Synthesis, characterization and biological evaluation of some novel P-heterocyclic androst-4-ene derivatives
VL  - 17
IS  - 3
SP  - 547
EP  - 561
DO  - 10.1007/s11030-013-9455-9
ER  - 
@article{
author = "Krstić, Natalija and Pavlović, Vladimir D. and Novaković, Irena and Matić, Ivana Z. and Sladić, Dušan",
year = "2013",
abstract = "The reactions of 21-hydroxyprogesterone with Lawesson's reagent in toluene or gave four P-heterocyclic androst-4-ene derivatives (two tautomeric pairs): 4-(3-thioxoandrost-4-en-17-yl)-1,3,2-oxathiaphosphole-2- sulfide (2), 4-(3-thioxoandrost-4-en-17-ylidene)-1,3,2-oxathiaphospholane-2-sulfide (3), 4-(3-oxoandrost-4-en-17-yl)-1,3,2-oxathiaphosphole-2-sulfide (4), and 4-(3-oxoandrost-4-en-17-ylidene)-1,3,2- oxathiaphospholane-2-sulfide (5). The structures of all novel 17-substituted steroids were elucidated from their analytic and spectral data (HRMS, IR, 1D NMR and 2D NMR-HSQC, HMBC, NOESY, COSY). The detailed NMR analysis for all compounds revealed the presence of two pairs of signals in approx. 8:2 ratio indicating the existence of two diastereoisomers (a and b) with different configurations at the phosphorus atom. A parallel analysis of heteronuclear 2D - spectra (HSQC and HMBC) and homonuclear 2D spectra (NOESY and COSY) enabled complete and assignments of each isomer and provided evidence for the preferred configuration on phosphorus atom. Cytotoxic activity in vitro was tested against four tumor cell lines (human cervix carcinoma HeLa cells, chronic myelogenous leukemia K-562 and two human breast carcinoma MDA-MB-361 and MDA-MB-453 cells). Compounds 3a,b and 4a,b showed a poor activity against HeLa and MDA-MB-453 cell lines, while against MDA-MB-361 cell line, all tested compounds exerted very weak cytotoxic effect. All compounds exerted moderate activity against K562 cells. Antimicrobial activity against Gram-positive, Gram-negative bacteria and fungal cells, and toxicity to brine shrimp Artemia salina were evaluated. All tested compounds showed strong antifungal activity.",
publisher = "Springer, Dordrecht",
journal = "Molecular Diversity",
title = "Synthesis, characterization and biological evaluation of some novel P-heterocyclic androst-4-ene derivatives",
volume = "17",
number = "3",
pages = "547-561",
doi = "10.1007/s11030-013-9455-9"
}
Krstić, N., Pavlović, V. D., Novaković, I., Matić, I. Z.,& Sladić, D.. (2013). Synthesis, characterization and biological evaluation of some novel P-heterocyclic androst-4-ene derivatives. in Molecular Diversity
Springer, Dordrecht., 17(3), 547-561.
https://doi.org/10.1007/s11030-013-9455-9
Krstić N, Pavlović VD, Novaković I, Matić IZ, Sladić D. Synthesis, characterization and biological evaluation of some novel P-heterocyclic androst-4-ene derivatives. in Molecular Diversity. 2013;17(3):547-561.
doi:10.1007/s11030-013-9455-9 .
Krstić, Natalija, Pavlović, Vladimir D., Novaković, Irena, Matić, Ivana Z., Sladić, Dušan, "Synthesis, characterization and biological evaluation of some novel P-heterocyclic androst-4-ene derivatives" in Molecular Diversity, 17, no. 3 (2013):547-561,
https://doi.org/10.1007/s11030-013-9455-9 . .

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