Synthesis and biological activity of several steroidal oximes

Full text of DOI:10.1007/s10600-010-9657-7

Chemistry of Natural Compounds, Vol. 46, No. 3, 2010
SYNTHESIS AND BIOLOGICAL ACTIVITY OF SEVERAL
STEROIDAL OXIMES
M. I. Sikharulidze,* N. Sh. Nadaraia, M. L. Kakhabrishvili,
N. N. Barbakadze, and K. G. Mulkidzhanyan
UDC 547.92
Steroidal oximes and their derivatives are known to exhibit anti-inflammatory, anticancer, and other types of
physiological activity [1, 2].
In continuation of structure–activity relationship studies of 5ꢀ-steroids [3], we synthesized steroidal oximes 1–7 and
studied their antimicrobial and anti-inflammatory activity.
The starting material for synthesizing 1–7 was 5ꢀ-pregnenolone acetate, which was prepared by the method developed
previously by us [4].
Oximes 1–6 were synthesized by the known method [5] from the corresponding ketones whereas 5ꢀ-pregnen-2-
one-20 (7) was obtained for the first time from ketone 8 using its tosylation (9), dehydrotosylation (10) [6, 7], and reaction of
10 with hydroxylamine hydrochloride in Py (Scheme 1).
CH
3
NOH
NOH
C
NOH
AcO
HO
AcO
H
H
H
1
2
3
NOH
NOH
NOH
HON
HON
4
6
5
H
H
CH
C
3
CH
C
3
NOH
O
TsO
HO
H
H
H
H
8
7
9
10
Scheme 1
The structures of the products were confirmed by IR and PMR spectral data and elemental analysis.
The PMR spectrum of 10 showed resonances for angular methyls C-18 and C-19 as singlets with chemical shifts
ꢁ 0.67 and 0.85 ppm, respectively. The chemical shift of methyl C-21 was 2.05 ppm. Of the other resonances, a complicated
multiplet near 5.52 ppm belonging to the C-2 and C-3 protons should be mentioned.
Introduction of the oxime (7) shifted resonances of all methyls to strong field (0.61, 0.74, and 1.86 ppm, respectively)
and caused the appearance of a C=N–OH resonance as a broad singlet at 8.28 ppm. The C-2 and C-3 protons of the double
bond resonated as a complicated multiplet at 5.56-5.58 ppm.
I. Kutateladze Institute of Pharmaceutical Chemistry, Tbilisi, 0159, ul. Saradzhishvili 36, fax: (99532) 52 00 23,
e-mail: docmadona@yahoo.com. Translated from Khimiya Prirodnykh Soedinenii, No. 3, pp. 414–415, May–June, 2010.
Original article submitted August 6, 2009.
©
0009-3130/10/4603-0493 2010 Springer Science+Business Media, Inc.
493

The biological activity of the steroidal oximes was predicted by the PASS (Prediction of Activity Spectra Substances)
computer program.
Antimicrobial, antifungal, anti-inflammatory, and antiatherosclerotic activity was most probable for all oximes
synthesized by us (1–7).
An in vitro experiment with 3,17-dihydroxyiminoandrost-4-ene (6) showed activity against several fungus strains
(Sporobolom salmonicolor, Candida glabrata, Penicillium notatum, Aspergillus terreus, A. niger, A. fumigatus) that was
comparable with that of amphotericin and nystatin.
Also, the predicted anti-inflammatory activity of 3ꢂ-hydroxy-17-hydroximino-5ꢀ-androstane (3) was consistent with
a biological experiment because 3 acted as a selective blocker of the enzyme cyclooxygenase-2. The other oximes (1, 2, 4, 5,
7) exhibited moderate or low activity.
A trial was performed at the Hans Knoll Institute of Natural Compounds and Infectious Biology (Germany). It was
found that a double bond, even moreso conjugated (6), enhanced the antimicrobial activity whereas an OH group on C-3 (3)
increased the anti-inflammatory activity of the steroidal oximes.
IR spectra were recorded in KBr disks on a Thermo Nicolet Avatar-370 spectrometer. PMR spectra were measured in
CDCl on a Bruker AM-400 (400 MHz) spectrometer; melting points, on a Boetius heating stage.
3
The course of reactions and purity of products were monitored by TLC on Silufol UV-254 plates using benzene:acetone,
6:1. Elemental analyses of all compounds agreed with those calculated.
3ꢂ-(4-Methylphenylsulfonyloxy)-5ꢀ-pregnan-20-one (9). A solution of ketone 8 (1 g, 3.1 mmol) in anhydrous Py
(3 mL) at 0–5°C was treated over 1 h with p-toluenesulfonylchloride (2 g, 10.1 mmol). The reaction mixture was stirred for
3 h at 20–25°C, treated with conc. HCl (3 mL), and held at 0–5°C for 5 h. The resulting precipitate was filtered off, washed
–1
with water, and dried. Crystallization from benzene produced 1.2 g (90%) of 9, mp 95–98°C. IR spectrum (ꢃ, cm ): 1740,
1680 (C=O), 1590 (C=C, Ar). PMR spectrum (ꢁ, ppm, J/Hz): 062 (3H, s, 18-CH ), 0.84 (3H, s, 19-CH ), 2.12 (3H, s,
3
3
21-CH ), 2.45 (3H, s, CH -Ar), 7.35 (2H, d, J = 8, H-Ar), 8.24 (2H, d, J = 8, H-Ar).
3
3
5ꢀ-Pregn-2-en-20-one (10). A solution of tosylate 9 (1.4 g, 2.9 mmol) in freshly distilled DMF (15 mL) was treated
with LiBr (1.2 g, 13.6 mmol) over 2 h, refluxed for 2 h, cooled to 20°C, and diluted with water (300 mL). The resulting
crystals were filtered off and washed with water to afford 0.7 g of crude product. Crystallization from MeOH afforded 10
–1
(0.4 g, 57%), mp 125–128°C. IR spectrum (ꢃ, cm ): 1710 (C=O), 1640 (C=C). PMR spectrum (ꢁ, ppm): 0.67 (3H, s,
18-CH ), 0.85 (3H, s, 19-CH ), 2.05 (3H, s, 21-CH ), 5.52 (2H, complicated m, H-2, H-3).
3
3
3
20-Hydroximino-5ꢀ-pregn-2-ene (7). A mixture of 10 (0.4 g, 1.3 mmol) and NH OH4HCl (0.1 g, 1.47 mmol) in Py
2
(5 mL) was heated at 65–70°C for 3 h, cooled to 20°C, and poured into icewater (50 mL). The precipitate was filtered off,
–1
washed with water, and dried to afford 7 (0.38 g, 90%), mp 113–115°C (MeOH). IR spectrum (ꢃ, cm ): 1680 (C=N), 1640
(C=C). PMR spectrum (ꢁ, ppm): 0.61 (3H, s, 18-CH ), 0.74 (3H, s, 19-CH ), 1.86 (3H, s, 21-CH ), 5.56 (2H, complicated m,
3
3
3
H-2, H-3), 8.28 (br.s, CN–OH).
ACKNOWLEDGMENT
The work was supported financially by the Georgian National Science Foundation (Grant No. GNSF/ST08/4-406).
We thank Dr. K. Lange for performing the biological experiments.
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