Mar.

Drugs 2005, 3, 84-111

Marine Drugs
ISSN 1660-3397
www. mdpi.net/marinedrugs/
Review
Sterol Ring System Oxidation Pattern in Marine Songes
Nittala S! Sarma"# M! Sri Rama $ris%na and S! Rama&ris%na Rao
School of Chemistry, Andhra Uniersity, !isa"hapatnam-#$% %%$, &ndia
'Author to whom correspondence should (e addressed) *el. %%+1-8+1-,844-.1,
/-mail0 nitt a l as1lyc o s. c om
Received: 31 January 2005 / Accepted: 7 June 2005 / Pu!is"ed: 7 June 2005
'(stra)t0 *he marine sponges 23orifera4 are a uni5ue group of sedentary organisms
from which seeral noel natural products are reported, many of which hae useful
(iological actiities. &n producing unusual sterols, they occupy a preeminent position
among the arious groups of organisms. *he polar sterols of sponges reported as at
the end of the year ,%%, num(er a(out ,#%) their ring structure changing a hundred
times. *he o6idation pattern in the sterol ring system, from the point of iew of
(iogenesis seems to (e mainly of four types. /ach sponge species is a(le to produce
sterols fitting into one of the four main (iogenetic pathways i7., 2i4 $8-hydro6y-9
#
-
sterol pathway, 2ii4 $8-hydro6y-9
.
-sterol pathway, 2iii4 $8-hydro6y-9
#,.
-sterol
pathway, and 2i4 $:-hydro6y sterol pathway.
$ey*ords0 ;arine sponges, 3olar sterols, Unusual sterols, <ing system, =6idation pattern
Introd+)tion
*he >usual? sterols hae the $8-hydro6y-9
#
2or 9
%
4-cholestane 2I4 nucleus and a C
8
-C
1%
side
chain @1A. *here are oer ,%% such sterols, occurring in marine organisms as comple6 insepara(le
mi6tures and their identification is usually done (y BC-;S. *he >unusual? sterols @,A hae either or
(oth of the characteristics of0 2i4 side chains ranging from C
%
to C
1,
inoling loss or addition of
car(on atoms at positions other than C-,4, and 2ii4 2multiple4 o6ygenation of the nucleus and/or the
Mar. Drugs 2005, 3 ,5
side chain. *hese sterols, (y irtue of their greater spread on the polarity scale, can (e isolated in pure
condition (y li5uid chromatography. Cut, many of them are ery unsta(le and should (e handled at
ery mild conditions so that artifacts are not mista"en as natural products.
*he polar sterols of sponges, particularly the sulfate esters 2Schemes 1,-144 hae interesting
and useful (iological actiities that ma"e them targets of (iological ealuation and synthesis.
Although polyhydro6y sterols hae (een found in arious groups of marine organisms e.g.,
algae, porifera, coelenterata, (ryo7oa, mollus"a, echinodermata, arthropoda, tunicata and chordata, a
preeminent position is occupied (y porifera, i.e., sponges. A full reiew of the marine polyhydro6y
steroids was pu(lished in 1++$ @$A. *he reiews that appeared since @4,#A discuss (riefly on sponge
sterols. *he present reiew?s purpose is (esides giing the account as of date, to descri(e for the first
time the (iogenetic relationships that possi(ly e6ist in the sterol nuclear structure. *his aspect may
hae a (earing on sponge classification, and the geographic occurrence of the organism, and (e of
great utility in chemota6onomic studies. Dor (reity, the structures of sterols are presented as part
structures, focusing on the o6idation pattern occurring in the sterol ACCE ring system 2alone4. A
single sterol nucleus, as shown in arious schemes 2Schemes $-144 may stand for a num(er of
indiidual steroids with structural changes occurring in the side chain that are, howeer, not shown.
&n order to propose (iosynthetic relationships, as marine (iosynthetic studies are few @-,.A,
clues are ta"en from the pathways operating in the terrestrial plants and animals, which are
documented 5uite well, and since the pathways operating in marine organisms should essentially (e
similar to those operating in terrestrial organisms @8A. &n Schemes 1-14 are presented se5uential
o6idations within the sterol ACCE ring system that should (e ta"ing place as part of (iogenesis within
marine sponges. &n each product structure, the center where the structural change has resulted
compared to the precursor is shown in red color. *he (iogenic connectiity (etween arious sterol ring
structures although hypothetical is depicted with the arrow 2F4 sign for clarity although this sign is
usually resered for chemical conersions that actually ta"e place. ;ost often, each sponge species
contains a particular group of polar sterols dominated (y a set of closely related (iogenetic
mechanisms as presented in each scheme. Goweer, since the schemes are formulated (asing on the
>reported? sterol composition, and since there is occasionally a lac" of information on the total sterol
composition of the sponge 2often, it is only the new compounds that are descri(ed4, the schemes are
su(Hect to refinement.
Seeral noel sterols containing e6tra o6ygen su(stitution and side chain modified (y
al"ylations/deal"ylations hae (een reported from marine sponges. &n 5uite a few species, noel sterols
are the 2single4 maHor components of their e6tracts. *ypical e6amples are aplysterol 2II4 and ,42,84-
didehydro aplysterol 2III4, the first sterols @+A with a methyl group at C-,-, which hae (een found as
the maHor sterols of the sponges of the genus Ap!ysia #$er%ngia&' calysterol 2I-4, the maHor sterol 2+%I
of the sterol mi6ture4 of the sponge (a!y) nicaensis @1%A, petrosterol 2-4 of the sponge Petr%sia
*ici*%r+is @11,1,A, strongylosterol 2-I4, the sole sterol of ,tr%ngy!%p"%ra durissi+a @1$A, and
6estosterol 2-II4 and sutinasterol 2-III4 isolated as the predominant sterols of -est%sp%ngia +uta @14A,
and -est%sp%ngia sp. @1#A respectiely.
4
4 6
N
Mar. Drugs 2005, 3 ,6
S
12 17
21
20
18
12 17
22 24 26
23 25
27
11 13 16
19
11 13 16
1
2
HO
3
9
10 8
5 7
6
14 15
1 9
2 10
HO
3 5
28 29
14 15
8
30
7
Cholesterol Ring System (N) !" l#nosterol
21 22 24
27
20 23 25
N
26
21 22
20
N
28
24 27
23 25
26 N
29

$
H
N N
$
$
29
N
30
$
30
31
32
N
$
.eneral (iosynt%eti) Rea)tions in marine songes
Jor"ing on the usual cholesterol s"eleton, sponges are capa(le of performing en7ymatic
o6idation around the actie sites, $8-=G and 9
#
functionalities.
1. epo6idation 2generally :: and rarely 884 followed (y its opening in different pathways,
,. o6idation of the allylic C-. and C-4 car(ons to gie simple alcohols of the preferred
configuration, and
$. isomerisation of the dou(le (ond2s4.
*he reactions that ta"e place on the $8-=G and the new =G groups that are introduced 2Scheme ,4 are0
1. o6idation to a car(onyl,
,. dehydration producing unsaturation which will create new actie allylic positions for
further o6idation,
$. retro Eiels-Alder reaction in the case of icinal diols, and
4. condensation reactions inoling =G, CG
,
=G, CG=, and C==G groups at appropriate
locations.
*hese reactions centering the 9
#
and the $8 -=G are shown in Schemes 1 and , respectiely.
%
S)%eme 1.Significant (iosynthetic reactions caused (y 9
#
2S K side chain) see also scheme 1%4
S
%
HO
HO
O
HO
O
& '
HO
HO
OH
(is
o)ening
HO
O
&
tr#ns
o)ening HO
HO
OH
%
HO
HO
OH
HO
HO OH
(is
o)ening
HO
O
'
tr#ns
o)ening
HO
R OH
%
HO
HO
OH
(on(erte*
HO
o)ening
O
&
HO HO
OH
OH
(on(erte*
HO
o)ening
O
'
%
HO
HO
OH
OH
HO
S)%eme 2! Significant (iosynthetic reactions caused around $8-=G) @ A intermediate.
2i4 *he -8L=G su(stituent present in a cis 1,$Ldia6ial manner to the C-1% ;e group can
o6idi7e it in a step-wise fashion.
HO
HOOC
HO
H
OH
HO
H
OH
HO
H
OH
2ii4 /pimerisation of the $8-=G can occur if actiated (y migration of 9
#
to 9
4
.
HO
HO HO
2iii4 *he 9
4
is amena(le for al"ylation.
HO
%
HO
&n the following account, the progression of (iosynthetic o6idatie reactions that should (e
operating on the sterol ring system is presented. *he pathways shown in the Schemes and discussed
in te6t refer only to the ring system and not the complete structure of the steroid, as the structure of
the side chain is not considered due to space constraint.
I! 9
5
-38-/ydroxy Steroids
3olar sterols in which the parent sterol nucleus is retained are 1 and 2 from (a!y) nicaensis @1-A
and (. p%datypa @1.A, and 3 recently from an &ndian sample of Petr%sia testudinaria @18A.
1. Oxidation at C-7 (Scheme 3)0 *he epimeric alcohols 1 and 5 and their "etone 6 are from
(%ra!!istes undu!atus @1+A and (!i%na c%pi%sa @,%A (y the allylic C-. o6idation. &t was for
some time suspected that the C-. o6idation might (e resulting from auto-o6idation during
isolation procedure. Gence, the isolation of the .:-glycoside 7 2paschastrelloside A4 from
Pasc"astre!!a sp. confirms a (iotic origin of the .: o6ygen @,1A. *he noel feature of 7 is
its ,:-=G) the sterol inhi(its cell diision of fertili7ed starfish eggs. *he presence of the
.:-=G and .-"eto group naturally in the sponge has receied further proof from the recent
isolation of a num(er of steroids ,-11 2gelliusterols A-E4 from .e!!ius sp. of the 3anaman
Cari((ean coast @,,A. Sterol 12 was isolated from P%!y+astia s%ustia from South China
Sea @,$A, as well as 11 @,4A, 13 from .e%dia /ap%nica also from South China Sea @,#A.
Sterols 15 and 16 are from a Mapanese specimen of ,tr%ngy!%p"%ra c%rticata @,-A, and 17
2polysterol A4 from 0pip%!asis sp. @,.A, and 1,-27 topsentinols A to M from an ="inawan
species of 1%psentia @,8A. *he sterol containing the nucleus 2, 2polysterol C (elonging to
another sterol su(class, the $:-hydro6y sterol sulfates0 Scheme 1$4 co-occurs with 29
2polysterol A4. Although for the $:-o6ygenated sterols also, the parent is the $8-9
#
-sterol
nucleus, the (iogenetic pathway is somewhat different. *he isolation of sterols (elonging to
different (iogenetic pathways may (e due to sym(ionts causing species heterogeneity or
artifact formation on preseration and the su(se5uent isolation procedure. Gence, it is
necessary to "now these factors well for rationali7ing the co-occurrence of sterols
(elonging to different (iogenetic classes. *he ,tr%ngy!%p"%ra c%rticata sterols may
e6emplify this dimension.
S)%eme 3! =6idations at C-. of 9
#
-$8-hydro6y steroid s"eleton
HO
HO OH
HO
HO
O+gly
O+gly
1"2"3 5","16"1,"19"
20"21"22"23"
21"25"26"27
7" gly0 gly)oside
HO OH
1
HO O
6"9"10"11"12"
13"11"15"17" 29
2. Oxidation confined to Ring (Scheme !)" *he alcoholic C-$ and allylic C-4 are actie
sites for o6idation. *he formation of $-"etone can facilitate migration of the 9
#
to the
conHugated 9
4
position, as found in 30, mycalone from Myca!e sp. of Southern Australia
@,+A. *he chloro"etones 31 and 32, "iheisterones C and / present in ,tr%ngy!aced%n sp.
from ;aui along with the chlorohydrin E 33 are the only halogenated sterols isolated from
sponges een though halogenated, particularly (rominated natural products are common in
marine sponges (eing deried from red algal sym(ionts. *he products of C-, actiation are
the diosphenols 31 2"iheisterone A4 and 35 2"iheisterone C4 of the same sponge @$%A. A
hydro6ylation of the allylic C-4 is demonstrated (y the $8-sulfo6ypregnane 36 isolated
S)%eme 1. 9
#
sterols0 =6idations in the ring A/C system) @ A 0 not isolated
HOOC
N#O
3
SO
N#O
3
SO
17" 1," 19 16
HO
O
O
Cl
HO
H
Cl
1" 2" 3
30 31" 32 33
O
O
HO
HO
OH
COOH
HO O
HO
OH O HO
11" 12" 13 31 35
S
S
OH
SO
O
HO
N#O
3
SO
OH
OH
gly+O
OH
15 11 36 37" gly0 gly)oside
HO
HO
O+,yl+g#l
3," 39" 10
xyl0 xylose2 gal0 gala)tose
from ,ty!%pus austra!is @$1A, and the glycoside 37 from Myca!e !a)issi+a @$,A. *he C-1 is
actiated via the 9
,
formation (y dehydration of the $8-=G. *he 9
,
, not so far o(sered in
sponge sterols is a routine feature in the highly o6ygenated sterol classes of withanolides
and physalins from land plants (elonging to the Solanaceae family @$$A. *he intermediate
9
,
can then indulge in icinal ,:,$8-diol and ,8,$8-diol formation, e.g., the glycosides 3,-
10, the wondosterols A, C and C isolated from a two sponge association of P%eci!!astra
w%nd%ensis and Japsis w%nd%ensis @$4A. Jith the ring A (ecoming o6ygen rich, the 1+8-
;e (ecomes amena(le for o6idation to LC==G group and conse5uent lactonisation with
the ,8-=G, as seen in the pregnane N-car(olactones 11-13 isolated from the Gawaiian
sponge ,tr%ngy!%p"%ra sp. @$#A. *he free C==G group can also disappear (y loss of C=
,
leading to ring-A aromatisation found in the sterols 11 geodisterol isolated from .e%dia sp.
from 3apua Oew Buinea @$-A, and the 1+-nor pregnane glycoside 15 from (rir%c"a!ina
%!e+da from 3ohnpei, ;icronesia @$.A. =6idatie elimination of the 1+-;e ta"es place
rather easily in sponges (elonging to A6inellideae, e.g., A)ine!!a p%!yp%ides, which
contains 16 as the important sterol @$8-4%A. &ts precursor A/C ring structure containing the
1+-C==G group is present in the sterols 17-19 isolated from 1%)ad%cia 2u+i @41A.
3. Oxidations and rearrangements in the '34 ring system 5S)%eme 560 &n sponges, ring A-
rearranged sterols cooccur with $-"eto sterols, and $,--diones, a phenomenon that is
particularly uni5ue in sponges (elonging to the families A6inellideae and
Gymeniacidonidae. *his is attri(uted to an efficient en7yme system due to which the A/C
ring reaction precedes o6idation at other centres, e.g., 9
1#
introduction in 50, and 9
14
-1-:-
=G system in 51 found in the sterols of A)ine!!a pr%!i*erans from <eunion island in the
&ndian =cean @4,A. *he (iosynthesis of the uni5ue 52 and 53 2anthosterones A and C
respectiely4 of Ant"%racurata gracia is suggested to ta"e place (y a (en7ilic acid
rearrangement of a ,,$-di"eto precursor as a new type of ring A contraction step @4$A.
S)%eme 5! 9
#
sterols0 $- Petosterols and rearranged sterols) @ A 0 not isolated) S 0 side chain
S
HO
OH
CHO
59
HO
1" 2" 3
HOH
2
C
HOH
2
C
50
S
HO
O
O
O HO OH
O
OH
S
OH
HOH
2
C
5, 51
HO
HOH
2
C
O O
O
O
NOH
52" 53 51 55" 56
*he 9
4
-$,--di"etosterols 51, with seeral conentional side chains are also from
Ant"%racurata gracia, the sponge from which anthosterones 52 and 53 are isolated @4$A.
*he $,--di"etones of .e%dia cyd%niu+ @44A and (inac"yra tarentina @4#A co-occur with the
more common $-"etones @4-A. *he --o6imino-$-"etones 55 and 56 were o(tained from a
mi6ture of (inc"yre!!a a!!%c!ada and (. api%n @4.A. *he #:,-:-dihydro6ylation is seen in
57 from ,pirastre!!a inc%nstans from &ndia @48A, and the -:,.8-dihydro6ylation is seen in
5, clathriol from (!at"ria !iss%sc!era @4+A of Oew Qealand. *he former seems to (e the
precursor of ring C rearranged 59 orostanal isolated from ,te!!ata "iwasaensis of Mapan @#%A.
*he sterol 59 is cytoto6ic and apoptosis-inducing.
!. Ring C oxidation (Scheme #)" *he ring C site of o6idation at C-1, may not (e re5uiring
actiation offered (y a 9
#
, a 9
.
or a $8-=G. *he saturated sterol 60 is in fact isolated in this
group from R"i2%c"a!ina incrustata @#1A. *he actiation seems to (e coming from the
heaily o6ygenated 2cyclopropane ring containing4 side chains, c.f., the potent antitumour
61 @#,A, and 62-61 @#$A from -est%sp%ngia sp., which are named aragusterols A to E, and
65 and 66 @#4A and 67 @##A named as 6estosterol A, 6estosterol C and aragusterol /
respectiely, from another -est%sp%ngia sp. collected from ="inawa. &n rare cases, a
further hydro6ylation occurs at C-., e.g., 6, 6esto"erol C) @#4A isolated along with
6esto"erols A, C and E and C-1-, e.g., 69 @##A, another aragusterol 2aragusterol D4 of the
-est%sp%ngia sp from ="inawa. *he s"eletons 70 and 71 are of aragusterols B and G
respectiely, also isolated from this collection @##A. *he sterols 72, and 73 are
aragustero"etals A and C respectiely that are also from the same sponge @#-A, and perhaps
artifacts of the isolation procedure.
S)%eme 6. 9
#
sterols0 <ing C o6idation in saturated sterols ) @ A 0 not isolated) S 0 side chain
OH S
HO
HO
O
O
O OH
1" 2" 3
60 61" 62" 63" 61"
6,
65" 66" 67
OH S
OH
OH S
71
OH S
OH
HO
70
OH
S
OH
O
69
-eO
-eO
72" 73
%
%
II! 9
7
-Sterols
*he parent $8-hydro6y-9
.
-sterol nucleus is present in 71 thymosiosterol and 75 2,4,,.-
didehydrothymosiosterol4 isolated from 1"y+%si%psis sp. from Drance @#.A, and 76 isolated from a
Cari((ean sponge ,c!erit%der+a sp. cf. paccardi @#8A.
1. Oxidation in$o%$ing C-7& C-'& C-(& C-11 and C-1! (Scheme 7)0 *he $8-hydro6y-#,--
dihydro-9
.
sterol nucleus seems to (e undergoing allylic C-+ and C-14 2of the isomerised
9
8
nucleus4 o6idation pathways. *he C-+ o6idi7ed 77 from Jeric%psis grap"idi%p"%ra @#+A
co-occurs with the C-14 o6idi7ed 7, and 79 @-%A.
S)%eme 7! 9
.
sterols0 =6idation inoling C-., C-8, C-+, C-11, and C-14 )
@ A0 not isolated0 S 0 side chain
HO OH
O
O
HO
HO
,0 ,3 ,1
HO
HO
HO
O O
HO
HO
71" 75" 76 77 ,5" ,7" ,, ,6" ,9
S
S
HO O HO
O
OH
HO
HO
,1 7, 79
S
S
OH
O
O
HO
90 ,2
2
*he 9
8
migrated to 9
82144
while 8:-=G is formed in ,0 isolated from Pe!!ina se+ituu!%sa
@,%A. *he 9
8
-.-"etone ,1 is from Jereic%psis grap"idi%p"%ra @#+A. *he 9
14
-1--:-hydro6y
sterol ,2 is from the ;editerranean sponge 1%psentia aurantiaca @-1A. /6tension of
unsaturation to 9
+2114
followed (y epo6idation is (ehind ,3 and ,1 @-,A. *he products of
retro Eiels-Alder reaction followed (y cyclic ether formation, i7., ,5-,7, and their $-
methyl ethers ,,, and ,9 are from Micr%sc!er%der+a spir%p"%ra from Senegal @-%A that co-
occur with the 8,14-seco-8,14-dione 90.
2. Stero% amines (Scheme ')" *he steroidal al"aloids, pla"inamines 91-95 are :-amino
"etones that are significantly cytoto6ic from a (%rticiu+ sp. from !anuatu @-$A. <ecently,
it is found that the amino"etones 2e.g., 96 pla"inamine D4 cooccur with the aminohydrins,
e.g., 97 2pla"inamine /4 in the (%rticiu+ sp. of Buam @-4A, and 9, in a !anuatuan
collection of the same sponge @-#A. *he amines 96 and 97 hae moderate cytoto6icity and
antifungal actiity, and nucleic acid-cleaing property. *hese aminohydrins pro(a(ly
formed via the addition of the elements of 2CG
$
4
,
O=G across a 9
$
which may (e
responsi(le for the amino"etones cited a(oe. *he $-amino steroids 99 and 100 that result
from the addition of OG
$
across 9
$
are also isolated from the !anuatuan collection @-#A.
S)%eme ,! 9
.
sterols0 Sterol amines) @ A 0 not isolated
HO
H
2
N
99" 100
-e
2
N
OH
%
-e N
OH
9, 97
-e
2
N
-e
2
N
O
O
91" 93" 91" 92
95" 96
III!9
5"7
-Sterols
;any sponge sterols are deried (y o6idation of the 9
#,.
-sterol nucleus. An intact $8-hydro6y-9
#,.
nucleus is present in the recently isolated 101 from the Mamaican sample of Age!as sceptru+ @--A.
1. )*idioxides (Scheme ()" /ndopero6ides are routinely prepared in the la(oratory (y the
action of singlet o6ygen on cyclic conHugated dienes. Gence, when the endopero6ides 102-
106 were isolated from 1et"ya aurantia @-.A and 102, 107 and 10, from A)ine!!a
cannaina @-8A, it was suspected that they might (e artifacts. Goweer, such epidio6ides
continue to (e isolated een when e6treme care is ta"en to preent their possi(le formation
during e6traction and isolation procedure. *hus, the ="inawan sponge A)inyssa sp. gae
109 a6inysterol @-+A, and 3enden*e!dia c"%ndr%ides from 3alau gae the antifouling sterols
110 and 111 @.%A. *he sponge species 3u**arie!!a cf. variai!is of Mapan gae a mi6ture of
the sterol epidio6ides 112-120, accompanied with the cytoto6ic 121, possessing e6tra 9
+2114
dou(le (ond @.1A, which system is also present in 122, recently isolated @.,A from the same
A)inyssa sp. that earlier gae 109 a6inysterol @-+A and which inhi(its the growth of seeral
human cancer cell lines.
S)%eme 9. 9
#,.
sterols0 /pidio6ides
HO
HO
O
HO
O
O
O
101
102" 103" 101" 105" 106" 107" 10,"
109" 110" 111" 112" 113" 111" 115"
116" 117" 11," 119" 120
121" 122
2. )*ox+ deri$ati$es of 9
,&7
s+stem (Scheme 1-)0 *he 1,,-o6ides of the 9
#,.
sterols are
predominantly :,:. *he intact epo6ide 123 and 121 its 9
82144
isomer, (oth haing
cytoto6icity to a range of human and murine cell lines are isolated recently @.$A from
P%!y+astia tena). *hese .:-alcohols are associated with the dienone 125 in the sponge.
*his typical dienone structure containing steroids were earlier isolated as 126, 127 and 12,
from (!at"rina c!at"rus @.4A. *he #:,-:-epo6y-.:-hydro6y-9
82144
system is also present in
129 isolated from an &ndian specimen of 4rcinia *ascicu!ata @.#A which should (e the
(iogenetic precursor of 130 @.-A. *he #:,-:-epo6y group opens up in a num(er of possi(le
ways 2see also Scheme 14, producing #:,-:-dihydro6y system, #:,-8-dihydro6y system,
and the #:-G,-:-hydro6y system. *he #8,-8-epo6ide system also occurs in which the $8-
=G had epimerised to $:-=G. *he opening of this epo6ide also proceeds in a num(er of
ways, e.g., #:,-8-dihydro6y system, #8,-:-dihydro6y system and #8-G,-8-hydro6y sterols.
&n each case, the 9
.
causes actiation of sites for further modification of the sterol structure.
%
%
%
S)%eme 10. 9
#,.
sterols0 /po6ides and deriaties) @ A 0 not isolated
O
OH
OH
HO
HO HO
HO
HO
HO
HO
HO
OH
HO
O
HO OH
O
HO
HO
O&(
HO
HO
OH
16
13, 137 15," 159"
160
HO
HOH
2
C
HO
HO
OH
HO O
HO
RO
HO O&(
O&(
HO
H OH
101
125"
126"
131" 150
HO HO
O
HO OH
%
HO
HO OH
HO
H
OH
136 119
HO
O OH
123
HO
O OH
121"
HO
O
O
R.O
HO
HO
HO
HO OH
139"
R7/
110
HO
HO
HO
HO
HO
HO OH
O
HO
HO O&(
131
HO
HO
HO
HO O&(
RO
H
OR.
OR..
O 153" R7/"
HO
RR7RRR7')
HO
155" R7RR7RRR7')
HO O&( 157" R7/"
132
130 111" 112"
113" 111"
115" 116"
133
HO
RO
H
OR.
OR..
151" R7RR7RRR7')
152" R7RR7')"
RRR7/
151" R7RR7')"
RRR7/
*he #:,-:-dihydro6y system is eidenced in sterols 131 @..A, 132 @.8A, and 133 @.+A which
are products of o6idation at e6tended sites. *he sterol 131 is from Dysidea sp. from
Oorthern Australia, and contains the additional +:,11:-epo6ide of a 9
+2114
, itself made
possi(le (y action from 9
8
. *he sterols that co-occur with 131 in the sponge are 131 and
135, in which the C-11 actiation is in eidence. *he sterols 131 and 135 inhi(it the
(inding of &S-8 to the human recom(inant &S-8 receptor type A. *he sterol 132, also
containing the +:,11:-epo6ide is from an unidentified species of Dysidea collected from
Buam @.8A. &n this sterol, the 1+-;e is additionally hydro6ylated. *he sterol 133 is from D.
"eraceae @.+A from /thiopia. *his sponge is uni5ue since each of the four sterols 136" 133"
137 and 13, isolated from it represents one type of #,--epo6ide 2or its opening4, i7., a
trans opening of the #:,-:-epo6ide, a cis opening of the #:,-:-epo6ide, a trans opening of
the #8,-8-epo6ide of the $:-hydro6y sterol and the #8,-8-epo6y-4:-hydro6y sterol itself
respectiely.
*he #:,-8-dihydro6y system is shown in addition to 136, in 139-11,. *he sterol 139 and
110 are from D. *ragi!is @8%A collected in the Clac" Sea. *he eight sterols 111-11, are from
D. et"eria from Cermuda @81A. *he #:-G,-:-hydro6y system is present in 119 @8,A and
150 @8$A. &t is also present in 151 o(tained from a Mapanese ,p%ngia sp. @84A which also
gae 152-157 @8#A. *he uni5ue feature of these si6 sterols is the presence of 48-o6ygen
function. Durther products of the #8,-8-epo6ide opening, in addition to 137 of Dysidea
"eraceae @.+A are the A/C cis 15,-160 o(tained from the same species of D. et"eria that
gae the A/C trans 111-11,) hence, the uni5ue a(ility of the two species of Dysidea. D.
"eraceae is further uni5ue for its 161 her(asterol @8-A, a #8-G-+2114-seco steroid, which is
ichthyoto6ic and antimicro(ial. *he cyclic ether 162 is from D. tup"a of the ;editerranean
@8.A.
3. ((11)-Seco Steroids0 A 9
+2114
actiation produces the +:,11:-icinal diol system which in
turn appears to (e responsi(le for the producion (y retro-Eiels Alder reaction, the +,11-
seco "etoaldehydes 163-165 luffasterols A, C and C present in 3u**arie!!a sp. from 3alau
@88A, 166 @4#A and 167 @8+A isolated from the ;editerranean sponge ,p%ngia %**icina!is.
*he "eto aldehyde 166 goes to the "eto alcohols 16, and 169 @4#A in the sponge. *he
epo6y "eto alcohol 170 glaciasterol C-$-acetate of 5asci%sp%ngia cavern%sa which is to6ic
to (rine shrimp, also from the ;editerranean @+%A, is howeer not associated with its
corresponding aldehyde as also in the case of 171 (lancasterol from the O/ 3acific sponge
P!erap!ysi!!a sp. @+1A from !ancouer and 172 from a Mapanese species of ,te!!etta @+,A. &n
the antihistaminic secosterols 173-1,2 of 0urysp%ngia sp. from Oew Caledonia @+$A) the ,-
=G which is usually 8 in this series is epimerised to :-=G.
95116- Se)o Steroids0
O
S
O
H
&(O
O
O
HO
H
OH
&(O
O
HO
OH
HO
S
HO
O
H
HO
H
HO
H
OH
163" 161" 165"
166 167
161
HO
S
O
HO O
HO
O
HO
HO
O
HO
HO
HO
&(O OH
O
HO
H
OH
HO
HO
H
OH
16," 169" 170 171 172 173" 171" 175" 176"
177 17," 179" 1,0"
1,1" 1,2
!. Oxidation not in$o%$ing ,:&#:-e*oxide (Scheme 11)0 *he reactions of the 9
#,.
system
without the mediation of the #:,-:-epo6ide come under this group, e.g., 1,3 from an
&ndian specimen of ,uerites carn%sus @+4A. =f particular significance is the methylation at
C-4, actiated (y 9
#
, as indicated (y the occurrence of 1,1 polymastiamides A @+#A, and
1,5-1,9 polymastiamides C to D in P%!y+astia a!eti*%r+is from Oorway, of which A, C,
E and D hae the 4:-;e su(stituent and C and / do not hae su(stitution at C-4 @+-A. *he
mildly cytoto6ic 190 from 1"e%ne!!a swin"%ei from 3hillippines, has instead a C-4
methylene group, a group that also occurs in the sterols 191-193 from 1. swin"%ei from
="inawa @+.A. &n 191 and 193, the 9
82144
underwent o6idation to gie the 8-14 seco-8,14-
dione. *he C-4 actiation leading to a 4:-o6ysulfate su(stitution is noticed in the ten
sterols 191-203 acanthosterol sulfates A to M from Acant"%dendri!!a sp. from Mapan @+8A. =f
these, 202 2acanthosterol sulfate &4 and 203 2acanthosterol sulfate M4 showed antifungal
actiity and cytoto6icity.
S)%eme 11! 9
#,.
sterols0 =6idation not inoling epo6ides) @ A 0 not isolated) S 0 side chain
HO O
HO
%
HO OH
HO N#O
3
SO
R
125
101 1,3
1,1" R7Me
1,5" R7/
1,6" R7Me
1,7" R7Me
1,," R7/
1,9" R7Me
S
HO
HO
OSO
3
H
O
%
O
HO OH
HO
191" 195" 196" 197" 19,"
199, 200" 201" 202" 203
190" 192
191" 193
I-! 3:-/ydroxy Steroids
*he mandatory configuration of the $-=G is 8
e5
for the (asic sterol s"eleton. Goweer, the
shifting of 9
#
to 9
4
can induce epimeri7ation of the $-=G to :
a6
, a cofiguration that gets sta(ili7ed (y
sulfate ester formation and 9
4
reduction in the sponge sterols.
1. 9
,
-Origin (Scheme 12)0 *he ring system of the sulfated steroids has a lone
representatie containing unsaturation in 201 @++A) all others are saturated, cf., 205
%alistanol C sulfate from Pac"astre!!a sp. @1%%A that inhi(its endothelium
conerting en7yme. Jein(ergsterols 206 2A4 and 207 2C4, hae hydro6ylation at
C-1- while wein(ergsterol C 20, has further hydro6ylation at C-18) they are isolated
from Petr%sia weiinergii @1%1,1%,A. *he disulfates 209, 210 and 207 are sterol
orthoesters inoling
1-8-=G 2and ,%-=G and ,,-=-(utyrate of the regular side chain4, isolated from the
same sponge. &n this group, the 1#:,1-8-dihydro6ylation is seen in 211 clathsterol with
anti G&!-1 reerse transcriptase actiity from an /ritrean sponge of genus (!at"ria
@1%$A. *he cytoto6ic and antifungal 212 echinoclasterol with heaily o6ygenated ring /
is from the south Australian sponge 0c"in%c!at"ria su"ispida @1%4A.
S)%eme 12. $:- o6ysteroids0 9
#
origin) @ A 0 not isolated, S K side chain
HO
HO
N#O
3
SO
N#O
3
SO
S
OH
O&(
211
N#O
3
SO
N#O
3
SO
N#O
3
SO
N#O
3
SO
201
H C H CH O
HO
S
OH
OH HO
S
OH
S
OH
N#O
3
SO
5 6 2 2
OH
HO
N#O
3
SO
212
20, 206" 207"
209" 210
205
3. 9
,&7
-Origin (Scheme 13)0 *he $:-sulfate esterification is more prolific when the genesis is
from the 9
#,.
sterol s"eleton. *he actiation of ring car(ons (y 9
.
seems to e6tend to C-1#:
(y migration of 9
.
to 9
82144
. &n this group, 213 is %alistanol sulfate from
6a!ic"%ndria +%%rei @++A which has potential actiity against G&! irus. &t is the
forerunner of seeral halistanol sulfates, e.g., 211-217 halistanols A to E from 0pip%!asis
sp. @1%#A, and 21, to
220, in vitr% G&! inhi(iting %alistanol sulfates D to G from Pseud%a)ynissa digitata
@1%-A. *he sterol 221 which showed inhi(ition in guanosine diphosphate/B protein <AS
e6change assay is ophirapstanol trisulfate from 1%psentia %p"irap"idites @1%.A. *he
sterol 222 is so"otrasterol sulfate isolated from two Galichondriidea species @1%8A,
and 223 is norso"otrasterol sulfate from 1rac"yp%sis "a!ic"%ndr%ides @1%+A. *he sterol
221 is from a Mapanese specimen of 1%psentia sp. @11%A. *he trio6ysulfate 29 polysterol
C sulfate of a
Mapanese specimen of 0pip%!asis sp. is accompanied in the sponge with 2, polysterol
A@,.A, a sterol that (elongs to group 1 as mentioned earlier 2Scheme $4.
S)%eme 13. $:-o6ysteroids09
#,.
origin) @ A 0 not isolated, S 0 side chain
RO
3
SO
RO
3
SO
%
OSO
3
R
N#O
3
SO
N#O
3
SO
S
OSO
3
N#
O&(
R7Na2 2," 213" 211"
215" 216" 217" 21," 219"
220" 221" 222" 223!
R7tris-52 amino-
imida8oli+m62 221
225
HO
HO
S
OH
HO
HO
OH
OH
S
OH
N#O SO
HO
HO
OH
OH
RO
HO
OH
OH
3
O
HO
H
OH
OH OH
229
R7/" 118-/2 22,
R7SO
3
Na" 118-/2 231
R7SO
3
Na" 11:-/2 232
226 230
S
S
OR.
H
O
HO OH
OH OH
N#O
3
SO
H
OR
OH OH
O/O
2
H-e
227
R7/" RR7 )y)li) *it% S2 233
R7PO
2
/Na"
RR7 )y)li) *it% S2 231
&n 0pip%!asis sp. @1%#A, the trio6ysulfates are associated with the product 225 of further
hydro6ylation at C-1#. *he 1#-"etosterol 226 6esto(ergsterol A, that inhi(its the release of
histamine from rat mast cells was isolated from -est%sp%ngia erg7uistii @111A. &t was earlier
isolated from 4rcinia sp. from ="inawa @11,A. *he simultaneous actiation of -: (y 9
4
and .8
and 1#: (y 9
82144
followed (y o6idation of the 1#-=G to 1#-"etone appears to (e ta"ing place
in 227 contignasterol @11$A. &n these 1#-"eto sterols, the configuration at C-14 is 148G as
opposed to the usual 14:G configuration. *he same 148G configuration is noticed in 22,
6esto(ergsterol C and the further 18-hydro6ylated steroid 229 6esto(ergsterol C from the
a(oe 4rcinia sp. *he sterol 230 with an additional 4:-=G from the ;alaysian 6a!ic!%na sp.
@114A and 231 from a new species of 8ceanapia @11#A also contain this ring structure. *he
sterol 231 is in fact accompanied with its 14:G epimer 232 in the sponge. Gence, a switchoer
of the original 14:G configuration to the more sta(le 148G is indicated in these "etones. *he
reduction thereafter of the 1#-"etone to 1#8-=G should (e responsi(le for 233 and 231 of two
3hilippine unidentified Gaplosclerid sponges @11-A.
3. 1!:-Meth+%ation (Scheme 1!)0 *he 14:-methylation is more common among tetracyclic
triterpenes of land plants, e.g., lanosterol 2-III4. *his feature, together with the 4,4-
dimethylation oer the C
1+
cholesterol nucleus gies the usual C
,,
tetracyclic triterpene nucleus.
S)%eme 11. 14:-;ethylation) @ A 0 not isolated, S 0 side chain
HO
101
HO
HO
O O
210
OH S
S
HO
N#O
3
SO
N#O
3
SO
235
HO
3
SO
HO
3
SO
OSO
3
H
N#O
3
SO
N#O
3
SO
OH OSO
3
N#
236" 237" 23," 239 211" 212" 213"
211" 215
*he 14:-sterols of sponges all possess a 9
+2114
-unsaturation indicating that (iological
methylation in these sterols (y 1,,-addition is facilitated in a homoannular-1,$-diene ring C as
shown in the Scheme 14, cf., 235 lem(ehsterol C with 9
#
retained from the &ndonesian
Petr%sia str%ngy!ata isolated together with the --=-sulfate ester i7., 236 lem(ehsterol A @11.A.
*his steroid ring system was earlier found in 237 i(isterol sulfate 2which is cytoprotectie
against the G&!-1 irus4 from 1%psentia sp. @118A and later also in 23, and 239, i(isterols C
and C of a 3hillippine sponge -est%sp%ngia sp. *hese two sterols are associated with the
"etoepo6ide 210 @11+A. *he sterols 23,, 239 and 210 are inhi(itors of G&!-& integrase. &n 211
to 215, topsentiasterol sulfates A to / isolated from an ="inawan 1%psentia sp. hae the
additional 48-=G group @1,%A.
9on)l+sions
As at the end of the year ,%%,, there are a(out ,#% polar sterols from marine sponges that
contain features of o6idation in the ring structure following a set pattern) the ring structure changing a
hundred times. Drom this pattern, the sponges are inferred to follow pathways that appear to (e
distinct and characteristic of the indiidual sponge species. *he marine sponges, in terms of their
a(ility to produce polar sterols appear to (e wor"ing on one of the four types of the sterol A/C ring
system i7., 2i4 9
#
-$8-hydro6y system, 2ii4 9
.
-$8-hydro6y system, 2iii4 9
#,.
-$8-hydro6y system and 2i4
$:-o6y-9
#
and $:-o6y-9
#,.
sterol systems. &n a few e6ceptional cases, a sponge may, howeer, contain
sterols (elonging to different classes, e.g., Dysidea "eraceae. Since the o(sered chemical
composition of a sponge may hae (een, in addition to the intrinsic nature of the sponge itself, due to
sym(ionts, ecological ariations, and isolation procedure, these changes should (e carefully considered
in trying to infer (iogenetic relationships. =nce this is done, it may (ecome possi(le to predict new
structures that can perhaps fit into the gaps of the (iogenetic se5uence of a gien sponge, (efore they
are actually isolated as natural products.
')&no*ledgements
Je than" ;r. S".B. 3asha, S<D, for technical assistance.
Re:eren)es and Notes
1. Boad, S.M. *he sterols of marine inerte(rates0 composition, (iosynthesis and meta(olites. &n0
Marine 9atura! Pr%ducts' ("e+ica! and :i%!%gica! Perspectives' $%!. 44" 197," Scheuer 3. M. /d.,
Academic 3ress, Oew Tor", pp .--1.,.
,. Schmit7 D.M., Uncommon marine steroids. &n0 Marine natura! pr%ducts' c"e+ica! and i%!%gica!
perspectives, $%!' 4, 197,, Scheuer 3. M. /d., Academic 3ress, Oew Tor" !ol. & pp ,41-,+..
$. E?Auria, ;.!.) ;inale, S.) <icco, <. 3olyo6ygenated steroids of marine origin ' ("e+. Rev. 1993,
+$, 18$+-18+#.
4. Stoni", !.A., ;arine polar steroids. Russ. ("e+. Rev., 2001, .%" -.$-.1#.
#. Pana7awa, A. Sterols in marine inerte(rate. 5is". ,ci. 2001, -. ++.-1%%..
-. Barson, ;.M. Ciosynthetic studies on marine natural products, 9at. Pr%d. Rep., 19,9, -, 14$-1.%.
.. Barson, ;.M., *he (iosynthesis of marine natural products. ("e+. Rev. 1993, +$, 1-++-1.$$.
8. *homas, <. Ciogenic speculation and (iosynthetic adances. 9at. Pr%d. Rep. 2001, ,1, ,,4-,48,
and earlier reiews.
+. Ee Suca 3.) Ee <osa ;.) ;inale S.) Sodano, B. ;arine sterols with a new pattern of side chain
al"ylation from the sponge Ap!ysina 2$er%ngia4 aer%p"%a. J. ("e+. ,%c. Per;in 1rans. &. 1972,
,1$,-,1$#.
1%. Dattorusso, /.) ;egno, S.) ;ayol, S.) Santacroce, C.) Sica, E. Calysterol0 A C
,+
cyclopropene-
containing marine sterol from the sponge (a!y) nicaensis. 1etra"edr%n 1975, $1, 1.1#-1.1-.
11. Sica, E.) Qollo, D. 3etrosterol, the maHor sterol with a cyclopropane side chain in the sponge
Petr%sia *ici*%r+is. 1etra"edr%n 3ett. 197,, 1+, 8$.-8$8.
1,. <ai, C. O.) Po""e, J.C.;.C.) Eelseth, C.) EHerassi, C. &solation and structure of ,-,,.-
cycloaplysterol 2petrosterol4 a cyclopropane-containing marine sterol. *etra"edr%n 3ett. 197,, 4#,
4$.+-4$8%.
1$. Cortolotto, ;.) Crae"man, M.C.) Ealo7e, E.) *ursch C. Chemical studies of marine inerte(rates
UUU!&, strongylosterol, a noel C-$% sterol from the sponge ,tr%ngy!%p"%ra durissi+a dendy.
:u!!. ,%c. ("i+. :e!g. 197,, 8., #$+-#4$.
14. Po""e, J.C.;.C.) *archini, C.) Stierle, E.C.) EHerassi, C. &solation, structure elucidation and
partial synthesis of 6estosterol, (iosynthetically significant sterol from the sponge -est%sp%ngia
+uta. J. 8rg. ("e+. 1979, 44, $$8#-$$88.
1#. Perr, <.B.) Perr, S.S.) 3ettit, B.<.) Garald, E.S.) Broy, *.S.) EHerassi C. Sterols of marine
inerte(rates. -$. &solation and structure elucidation of sutinasterol, the maHor sterol of the marine
sponge -est%sp%ngia sp. J. 8rg. ("e+. 1991, #-, #8--,.
1-. Si, S.O.) Si, G.*.) Sang, <.J.) &toh, *.) Sica, E.) EHerassi, C. ;inor and trace sterols in marine
inerte(rates. $1. &solation and structure elucidation of ,$G-isocalysterol, a naturally occurring
cyclopropene. Some comparatie o(serations on the course of hydrogenolytic ring opening of
steroidal cyclopropenes and cyclopropanes. J. A+. ("e+. ,%c. 19,2,1%4, -.,---.$,.
1.. Eoss, B.A.) EHerassi, C. Sterols in marine inerte(rates. -%. &solation and structure elucidation of
four new steroidal cyclopropenes from the sponge (a!y)p%datypa. J. A+. ("e+. ,%c. 19,,, 11%,
81,4-81,8.
18. <eddy, O. S., <amesh, 3.) !en"ateswarlu, T. A noel CV,. nor steroid from the marine sponge
Petr%sia testudinaria. 9at. Pr%d. 3ett. 1999, 14, 1$1-1$4.
1+. Buerriero, A.) E?Am(rosio, ;.) Dransesco, 3.) Ee(itus, C.) <i(es, =. 3teridines, Sterols, and
indole deriaties from the Sithistid sponge (%ra!!istes undu!atus of the coral sea. J. 9at. Pr%d.
1991, #-, 1+-,-1+.%.
,%. Ootaro, B.) 3iccialli, !.) Sica, !.) 3ron7ato, <. Oew 9
82144
-$8,.:-dihydro6ysterols from the
marine sponge Pe!!ina se+ituu!%sa. J. 9at. Pr%d. 1992, ##, ..$-..+.
,1. Girota, S.G.) *a"ayama, S.) ;iyashiro, T.) =7a"i, S.&. Structure of a noel steroidal saponin,
pachastrelloside A, o(tained from a marine sponge of the genus Pac"astre!!a. 1etra"edr%n 3ett.
1990, $1, $$,1-$$,4.
,,. Ballimore, J.A.) Pelly, ;. and Scheuer, 3.M. Belliusterols A-E, new acetylenic sterols from a
sponge, .e!!ius Species. J. 9at. Pr%d. 2001, -4, .41-.44.
,$. Uu, S.G.) Qeng, S.;. Study on the chemical constituents of marine sponge P%!y+astia s%ustia.
<%u/i 6ua)ue. 2001, ,1, 4#-48.
,4. Uu, S.G.) Qeng, S.;. *he identification of two new sterols from marine organism P%!y+astia
s%ustia. ("in. ("e+. 3ett. 2000, 11, #$1-#$4.
,#. Qhang, J.) Che, C. &somala(aricane-type nortriterpenoids and other constituents of the marine
sponge .e%dia /ap%nica. J. 9at. Pr%d. 2001" -4, 148+-14+,.
,-. Umeyama, A.) &to, S.) Toshiga"i, A.) Arihara, S. *wo new ,-,,.-cyclosterols from the marine
sponge ,tr%ngy!%p"%ra c%rticata. J. 9at. Pr%d. 2000, -$, 1#4%-1#4,.
,.. Umeyama, A.) Adachi, P.) &to, S.) Arihara, S. Oew ,4-isopropylcholesterol and ,4-
isopropenylcholesterol sulfate from the marine sponge 0pip%!asis species. J. 9at. Pr%d. 2000, -$,
11.#-11...
,8. &shi(ashi, ;.) Tamagishi, /.) Po(ayashi, M. *opsentionols AWM, new sterols with highly (ranched
side chains from marine sponge 1%psentia sp. ("e+. P"ar+. :u!!. 1997, 4#, 14$#-14$8.
,+. <ochfort, S.M.) Ba(le, <.J.) Capon, <.M. ;ycalone0 a new steroidal lactone from a southern
Australian marine sponge, Myca!e sp. Aust. J. ("e+. 1996, 4+, .1#-.18.
$%. Carney, M.<.) Scheuer, 3.M.) Pelley-Corges, ;. *hree unprecedented chloro steroids from the
;aui sponge ,tr%ngy!acid%n sp.0 "iheisterones C, E, and /. J. 8rg. ("e+. 1993, #8, $4-%-$4-,.
$1. 3rinsep, ;.<.) Clunt, M.J.) ;urray, G.) ;unro, B. A new sterol sulfate from the marine sponge
,ty!%pus austra!is. J. 9at. Pr%d. 19,9, #,, -#.--#+.
$,. Palinos"y, A.&.) Antono, A.S.) Afiyatullo, S.S.) Emitreno", 3.S.) /tuschen"o, /.!.) Stoni",
!.A. ;ycaloside A, a new steroid oligoglycoside with an unprecedented structure from the
Cari((ean sponge Myca!e !a)issi+a. 1etra"edr%n 3ett. 2002, 4$, #,$-#,#.
$$. Pirson, &.) Blotter, /. <ecent deelopments in naturally occurring ergostane-type steroids. A
reiew! J. 9at. Pr%d. 19,1, 44, -$$--4..
$4. <yu, B.) Choi, C.J.) See, C.G.) Gwang, P.G.) See, U.C.) Meong, E.S.) See, O.G. Jondosterols
A-C, three steroidal glycosides from a Porean marine two-sponge association. 1etra"edr%n 1999,
##, 1$1.1-1$1.8.
$#. Corgiat, M.;.) Scheuer, 3.M.) <ios Steiner, M.S.) Clardy, M. *hree pregnane-1%,,-car(olactones from
a sponge, ,tr%ngy!%p"%ra sp. 1etra"edr%n 1993, 4+, 1##.-1#-,.
$-. Jang, B.T.S.) Crews, 3. Beodisterol, a noel polyo6ygenated sterol with an aromatic A ring from
the tropical marine sponge .e%dia sp. 1etra"edr%n Sett. 1996, $., 814#-814-.
$.. Teung, C.P.S.) Gamann, ;.*.) Scheuer, 3.M.) Pelly-Corges, ;. Gapaioside0 A 1+-norpregnane
glycoside from the sponge (rir%c"a!ina %!e+da. 1etra"edr%n 1991, #%, 1,#+$-1,#+8.
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