Photochemistry of desonide, a non-fluorinated steroidal anti-inflammatory drug

Article abstract of DOI:10.1248/cpb.54.836

The photochemistry of anti-inflammatory drug desonide (De, 1) was studied in aerobic as well as in anaerobic condition with different irradiation wavelengths (254, 310 nm) in acetonitrile and 2-propanol. All photoproducts obtained were isolated and characterized on the basis of IR, ¹H-, ¹³C-NMR spectroscopy and elemental analysis study. The products were: 11β,21-dihydroxy-16α,17α-(1-methylethylidenedioxy)-1,5- cyclopregn-3-ene-2,20-dione 2 (254 nm), 11β-hydroxy-16α,17α-(1- methylethylidenedioxy)androsta-1,4-diene-3-one 3 (310 nm/2-propanol), 17β-hydroperoxy-11β-hydroxy-16α,17α-(1- methylethylidenedioxy)androsta-1,4-diene-3-one 4 (310 nm/O₂/2- propanol). Cyclohexadienone moiety in ring A and keto group at C₁₇ were found to be deeply modified by UV light therefore, loss of biological activity both during storage and in vivo can not be ruled out.

Full text of DOI:10.1248/cpb.54.836

836
Chem. Pharm. Bull. 54(6) 836—838 (2006)
Vol. 54, No. 6
Photochemistry of Desonide, a Non-fluorinated Steroidal
Anti-inflammatory Drug
Jawaid IQBAL,* Adil HUSAIN, and Anamika GUPTA
Department of Chemistry, Organic Chemistry Section, Aligarh Muslim University; Aligarh 202002 (U.P), India.
Received January 9, 2006; accepted March 8, 2006
The photochemistry of anti-inflammatory drug desonide (De, 1) was studied in aerobic as well as in anaero-
bic condition with different irradiation wavelengths (254, 310 nm) in acetonitrile and 2-propanol. All photoprod-
1
ucts obtained were isolated and characterized on the basis of IR, H-, 13C-NMR spectroscopy and elemental
analysis study. The products were: 11b,21-dihydroxy-16a,17a-(1-methylethylidenedioxy)-1,5-cyclopregn-3-ene-
2,20-dione 2 (254 nm), 11b-hydroxy-16a,17a-(1-methylethylidenedioxy)androsta-1,4-diene-3-one 3 (310 nm/2-
propanol), 17b-hydroperoxy-11b-hydroxy-16a,17a-(1-methylethylidenedioxy)androsta-1,4-diene-3-one 4 (310
nm/O2/2-propanol). Cyclohexadienone moiety in ring A and keto group at C17 were found to be deeply modified
by UV light therefore, loss of biological activity both during storage and in vivo can not be ruled out.
Key words photochemistry; desonide; anti-inflammatory drug
Polyfunctional molecules in which different photochemi- dienone moiety in ring A and an isolated ketone at C20. A
cally reactive chromophores are connected by rigid hydrocar- number of photochemical studies have been carried out on
bon framework are a subject of fascinating photochem- these steroidal ketones, both in solution and in solid state.16—22)
istry.1—3) The intramolecular energy transfer (both singlet– The photochemistry of cross-conjugated cyclohexadienone
singlet and triplet–triplet) may occur from an ‘antenna’ has been intensively studied because of their facile and fasci-
group to other chromophore leading to chemistry different natingly complex photochemical reactions. Williams et al.23)
from that observed by direct excitation of that chro- carried out photolysis of prednisolone, a molecule struc-
mophore.4—7) In the photochemistry of such multichro- turally related to De, at 254 nm and observed that only photo-
mophoric molecules the evaluation of interaction between the process occurring in dioxane solution was the “lumiketone”
chromophores, the mode and extent of local reaction at any rearrangement of the cyclohexadienone moiety. With this in-
chromophore after electronic excitation and possible role of terest, herein we have investigated the photochemistry of
energy transfer is of high mechanistic significance.
desonide under different combinations of solvents and irradi-
Morrison established, through a series of elegant papers,4—7) ation wavelengths.
that intramolecular energy transfer (both singlet–singlet and
triplet–triplet) occurred from the phenyl ‘antenna’ to C17 keto
Experimental
Chemicals and Instrumentation All chemicals used were of analytical
group in the steroids by the way of through-bond mechanism.
This lead to a different photochemistry observed by the di-
rect excitation of ketone chromophore. Albini et al.8,9) have
demonstrated non-communicating reaction paths in some
pregna-1,4-diene-3,20-dione. Since many steroidal drugs are
commonly used and several reports on their phototoxic
effects have been reported,10—13) it was of interest to exten-
sively study the aspect of competition between chemical
reactions of the separated excited moieties incorporated in
the rigid skeleton of the steroids. It was expected that such
photochemical mechanisms might have some relevance for
the mechanism of phototoxicity.
Glucocorticosteroids are natural hormones with a steroidal
structure derived from 5a-pregnane. These steroidal hor-
mones with powerful anti-inflammatory effects are secreted
by the cortex of adrenal gland. Semisynthetic derivatives of
these hormones are widely used as drugs to treat inflamma-
tory illness, including arthritis and asthma, and many of them
are effective by topical use in dermatoses and other dermato-
logical disease.
grade and were used as such without any further purification. Pure desonide
was obtained from Galderma Pvt. Ltd. (Mumbai, India). Irradiations at
254 nm were carried out in an immersion well type photoreactor (quartz)
equipped with 20 W low-pressure mercury arc lamp. For irradiations at
310 nm the solutions were irradiated with 15 W phosphor coated lamps. IR
spectra were recorded as KBr discs on a Perkin Elmer model spectrum RX1.
1H- and 13C-NMR spectra were recorded on a Bruker DRX-300 spectrome-
ter using SiMe4 as internal standard and CDCl3 as solvent. Circular dichro-
ism spectra were measured on a Jasco-J 41A spectropolarimeter. High reso-
lution mass spectra were determined with a VG-ZAB-BEQ9 spectrometer at
70 eV ionization voltage. Merck silica gel 60 F254 plates were used for ana-
lytical TLC; column chromatography was performed on Merck silica gel 60
(70—230 mesh).
Photoirradiation Procedure De solution (in acetonitrile or 2-propanol)
was stirred and flushed with argon or oxygen (as desired) for 1 h before irra-
diation and was kept bubbling during the irradiations. The course of reaction
was monitored by thin layer chromatography on precoated silica gel TLC
plates using chloroform–acetone mixtures. After the completion of reaction
(when desired conversions have reached) the solvent was removed in a ro-
tary evaporator and products were purified by silica gel column chromatog-
raphy.
Irradiation of De in Argon-Saturated Acetonitrile A solution of De
(210 mg, 0.5 mM) in argon-saturated acetonitrile (400 ml) was irradiated for
2.5 h at 254 nm. After following the steps described in general photoirradia-
tion procedure and column chromatography (cyclohexane–ethyl acetate),
compound 2 was obtained as product.
Desonide (De,1) is a synthetic nonfluorinated corticos-
teroid for topical dermatological use. It is used to treat in-
flammation caused by a number of conditions such as aller-
gic reactions, asthma and psoriasis.14,15) Desonide is very in-
teresting from photochemical point of view because it bear
two spatially separated chromophores i.e. cross conjugated
11b,21-Dihydroxy-16a,17a-(1-methylethylidenedioxy)-1,5-cyclopregn-
3-ene-2,20-dione (2): Yield: 115 mg (55%); HR-MS Calcd for (Mꢀ) C24H32-
O6 416.5073, Found 416.5065; IR (KBr) 3410, 1680 (CꢁO), 1565 (CꢁC),
1
1355, 1160, 1022 cmꢂ1 (cyclopropyl); H-NMR (DMSO-d6) d: 7.24 (d,1H,
Jꢁ6 Hz, H-4), 5.98 (d, 1H, Jꢁ6 Hz, H-3), 4.87 (br s, 1H, exch., OH), 4.69
∗ To whom correspondence should be addressed. e-mail: jawaid.iqbal0@lycos.com
© 2006 Pharmaceutical Society of Japan

June 2006
837
(s, 2H, H-21), 4.10 (t, 1H, H-16), 3.98 (br s, exch., OH), 3.16 (dd, 1H, Jꢁ 2-propanol) was irradiated at 310 nm two products were ob-
11,5 Hz, H-11), 1.82 (s, OC(CH3)2, 6H), 1.6—1.8 (m, 5H), 1.2—1.5 (m,
tained in both the solvents, which were identified as 2 and 3.
At the same irradiation wavelength (310 nm) saturation of
the solution with oxygen affected the product distribution: in
6H), 1.16 (s, 3H, H-19), 1.08 (s, 1H, H-1), 0.95 (s, 3H, H-18); 13C-NMR
(DMSO-d6) d: 211.4 (C-20), 193.2 (C-2), 132.5 (C-3), 158.1 (C-4), 109.2
(OC(CH3)2), 98.7 (C-17), 81.4 (C-16), 65.2 (C-11), 64.6 (C-21), 58.2 (C-9),
2-propanol 3 was not formed; instead hydroperoxide 4 was
obtained as main product along with trace amount of 2.
Whereas in acetonitrile a complex mixture of products was
obtained (Chart 1).
47.4 (C-1), 48.2 (C-14), 40.4 (C-12), 36.6 (C-13), 35.1 (C-6), 32.1 (C-5),
29.9 (C-10), 27.4 (C-8), 26.0 (C-15), 25.3 (C-7), 20.8 (C-19), 14.4 (C-18).
A solution of De (210 mg, 0.5 mM) in argon-saturated acetonitrile (400 ml)
was irradiated for 2 h at 310 nm. After following the steps described in
general photoirradiation procedure and column chromatography (cyclo-
hexane–ethyl acetate), compound 3 was obtained as the main product along
with a trace amount of 2 as detected on TLC.
11b-Hydroxy-16a,17a-(1-methylethylidenedioxy)androsta-1,4-diene-3-
one (3): Yield: 105 mg (50%); HR-MS Calcd for (Mꢀ) C22H30O4 358.4712,
Found 358.4718; IR (KBr) 3500, 1670, 1625, 1610; 1H-NMR (DMSO-d6) d:
7.52 (d, Jꢁ8 Hz, 1H, H-1), 6.14 (d, 1H, Jꢁ8 Hz, H-2), 6.03 (s, 1H, H-4),
3.92 (m, 1H, H-16), 3.87 (d, Jꢁ5 Hz, 1H, H-17), 3.40 (br s, 1H, exch., OH),
3.26 (m, 1H, H-11), 1.6—2.0 (m, 6H), 1.4—1.6 (m, 5H), 1.37 (s, 3H, H-19),
1.31 (s, 6H), 1.16 (s, 3H, H-18); 13C-NMR (DMSO-d6) d: 185.8 (C-3), 168.3
(C-5), 155.4 (C-1), 128.4 (C-2), 124.2 (C-4), 113.3 (OC(CH3)2), 80.4 (C-
16), 103.3 (C-17), 66.7 (C-11), 59.0 (C-9), 46.7 (C-14), 43.1 (C-12), 34.4
(C-10), 33.6 (C-6), 32.0 (C-7), 31.6 (C-13), 29.9 (C-8), 28.7 (C-15), 26.6
(OC(CH3)2), 25.7 (C-19), 17.3 (C-18).
These results can be rationalized on the basis of different
mechanism of photochemical reaction of the two-separated
chromophores present in this drug. At 254 nm, cross-conju-
gated ketone absorbs predominantly or exclusively, which
causes the well known lumiketone rearrangement24,25) of this
chromophore and leads to the formation of compound 2
(Chart 2). The rearrangement leading to 2 is a concerted
process and therefore not affected by the medium. On the
contrary at 310 nm, where isolated ketone at C20 absorbs a
large fraction of light, compound 3 was obtained as product
which arises via Norrish Type I homolytic photocleavage of
Irradiation of De in Oxygen Saturated Acetonitrile A solution of De
(210 mg, 0.5 mM) in oxygen-saturated acetonitrile (400 ml) was irradiated
for 2.5 h at 254 and 310 nm. After following the steps described in general
photoirradiation procedure and column chromatography (cyclohexane–ethyl
acetate), compound 2 (140 mg, 67%) was obtained as product at 254 nm
whereas a complex mixtures of products was obtained at 310 nm.
Irradiation of De in Argon-Saturated 2-Propanol A solution of De
(210 mg, 0.5 mM) in argon-saturated 2-propanol (400 ml) was irradiated for
2 h at 254 and 310 nm. After following the steps described in general pho-
toirradiation procedure and column chromatography (cyclohexane–ethyl ac-
etate), compound 2 (130 mg, 62%) was obtained as major product at 254 nm.
Whereas at 310 nm both the compounds 2 and 3 were obtained as products.
Irradiation of De in Oxygen-Saturated 2-Propanol A solution of De
(210 mg, 0.5 mM) in acetonitrile (400 ml) was irradiated for 2.5 h at 254 and
310 nm. After following the steps described in general photoirradiation pro-
cedure and column chromatography (cyclohexane–ethyl acetate), compound
2 (135 mg, 64%) was obtained as product at 254 nm. At 310 nm 2 (55 mg,
26%) and 4 (110 mg, 52%) were obtained as products.
17b-Hydroperoxy-11b-hydroxy-16a,17a-(1-methylethylidenedioxy)an-
drosta-1,4-diene-3-one (4): Yield: 110 mg (52%); HR-MS Calcd for (Mꢀ)
C22H30O6 390.4700, Found 390.4694; IR (KBr) 3400, 1655, 1620, 1600; 1H-
NMR (DMSO-d6) d: 8.9 (br s, exch., OOH), 7.56 (d, Jꢁ8 Hz, 1H, H-1), 6.18
(d, 1H, Jꢁ8 Hz, H-2), 6.08 (s, 1H, H-4), 4.12 (m, 1H, H-16), 4.82 (br s, 1H,
exch., OH), 2.2—2.6 (m, 4H), 1.2—1.9 (m, 6H), 1.4 (s, 3H), 1.3 (s, 3H), 1.2
(s, 3H); 13C-NMR (DMSO-d6) d: 192.0 (C-3), 167.1 (C-5), 156.4 (C-1),
125.7 (C-2), 124.4 (C-4), 121.5 (C-17), 105.4 (OC(CH3)2), 73.8 (C-16), 67.1
(C-11), 58.6 (C-9), 40.8 (C-14), 37.1 (C-10), 36.2 (C-12), 33.1 (C-6), 31.9
(C-7), 30.4 (C-13), 29.6 (C-8), 22.8 (C-15), 26.4 (OC(CH3)2), 25.4 (C-19),
17.5 (C-18).
Chart 1
Triphenylphosphine (26 mg) was added to a solution of hydroperoxide 4
(20 mg) in dichloromethane (20 ml) and stirring was pursued for 2 h, when
the starting material was consumed, extraction with water and evaporation
gave 15 mg of Compound 5.
Chart 2
11b,16a-Dihydroxyandrosta-1,4-diene-3,17-dione (5): HR-MS Calcd for
(Mꢀ) C19H24O4 316.3915, Found 316.3920; IR (KBr) 3450, 1745, 1660,
1
1600; H-NMR (DMSO-d6) d: 7.31 (d, Jꢁ8 Hz, 1H, H-1), 6.42 (d, 1H, Jꢁ
8 Hz, H-2), 6.01 (s, 1H, H-4), 4.98 (br s, 1H, exch., OH), 4.10 (m, 1H, H-
16), 4.01 (br s, 1H, exch., OH), 2.5 2.8 (m, 3H), 1.7 2.4 (m, 5H), 1.3 1.7 (m,
4H), 1.41 (s, 3H), 0.98 (s, 3H); 13C-NMR (DMSO-d6) d: 205.4 (C-17), 181.3
(C-3), 165.2 (C-5), 152.5 (C-1), 130.1 (C-2), 127.2 (C-4), 75.2 (C-16), 67.4
(C-11), 58.3 (C-9), 40.8 (C-10), 40.4 (C-19), 39.7 (C-13), 36.7 (C-14), 32.0
(C-6), 31.5 (C-8), 30.5 (C-12), 29.6 (C-7), 27.7 (C-15), 21.2 (C-18).
Results and Discussion
Irradiation of De at 254 nm in argon flushed acetonitrile or
in oxygen-saturated solution gave compound 2 as product.
The photoreaction of De in 2-propanol at 254 nm followed a
similar course of reaction under aerobic as well as anaerobic
conditions. When argon flushed De solution (acetonitrile or
Chart 3

838
Vol. 54, No. 6
Table 1. Circular Dichroism Spectra of 2 and Other Related Lumiproducts
Compd.
l
max (De)
l
max (De)
Crossover l
l
max (De)
Crossover l
l
max (De)
2
343 (ꢂ4.71)
313
309
278 (ꢀ12.22)
272 (ꢀ10.3)
253
250
225 (ꢂ11.71)
Short
wavelength –ve CD
Related
357 (ꢂ3.71)
344.5 (ꢂ3.77)
lumiproductsa)
a) See refs. 26, 27.
Chart 4
C17–C20 bond followed by hydrogen atom abstraction by References
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1
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1
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1
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