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Scien i ic RepoR s | 6:33908 | DOI: 10.1038/s ep33908
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No el and Neu op o ec i e
Te ano i e penoids om Chinese
Mang o e Xyloca pus g ana um
Koenig
Zhen-Fang Zhou1, Tibo Ku án2, A ila Mándi2, Yu-Cheng Gu3, Li-Gong Yao3, Guo-Rong Xin4,
Xu-Wen Li1 & Yue-Wei Guo1
Eigh new e ano i e penoids (1–8) we e isola ed om he wigs and lea es o he Chinese
mang o e plan Xyloca pus g ana um, oge he wi h ou ela ed known ones (9–12). The s uc u es
o new compounds we e elucida ed by de ailed spec oscopic analysis. The absolu e con igu a ion
o 9-epixylog ana in A (1) was de e mined by ime-dependen densi y unc ional heo y-elec onic
ci cula dich oism (TDDFT-ECD) calcula ions o he solu ion con o me s. Xylog ana umin A (2)
ep esen s he i s example o he 9, 10-seco limonoid wi h an unp eceden ed oxygen-b idged B ing
(2,7-dioxabicyclo[2.2.1]-hep ane). All he isola es we e e alua ed o he in i o neu op o ec i e
ac i i y, bo h compounds 11 and 12 displayed mode a e e ec s agains H2O2-induced neu o oxici y
in PC12 cells a he concen a ion o 10 μM, wi h an inc ease in cell iabili y o 12.0% and 11.6%,
espec i ely.
The mang o e plan s o he genus Xyloca pus ( amily Meliaceae) a e widely dis ibu ed in he coas al a eas o
Sou heas Asia, Aus alia, Eas A ica, and Indian Ocean. X. g ana um, one o he h ee Xyloca pus species, has
been used as a olk medicine in Sou heas Asia and India o he ea men o dia hea, chole a and e e dis-
eases1,2. X. g ana um was epo ed as a ich sou ce o limonoids, ea u ing by hei highly di e se and complex
polycyclic skele ons3–6. These s uc u ally in e es ing and challenging molecules ha e a ac ed g ea a en ion o
hei o al syn hesis, bioac i i y e alua ion, and biosyn he ic s udies7,8.
In he cou se o ou ongoing sea ch o bioac i e subs ances om Chinese mang o e plan s9–13, he wigs
and lea es o X. g ana um we e ecen ly collec ed om Hainan P o ince, China. A p elimina y chemical in es-
iga ion o hem has led o he isola ion and cha ac e iza ion o he ea anged py idine-con aining limonoids,
ph agmalin o hoes e s, and apo i ucallane p o olimonoids14–16. To u he explo e he bioac i e compounds
in X. g ana um, we con inued he phy ochemical analysis on he mino componen s in i s wigs and lea es,
esul ing in he isola ion and s uc u e elucida ion o eigh new e ano i epenoids, named 9-epixylog ana in
A (1), xylog ana umin A (2), 6-O-ace yl xyloca pin D (3), 14-hyd oxy-14,15-dihyd og ana umin C (4),
30-O- igloylhainang ana umin J (5), 9-O-me hyl xylog ana in R (6), 30-O-ace ylhainang ana umin E (7), and
1,2-dihyd o-3α-hyd oxy- u anolide (8), along wi h ou ela ed known compounds (9–12) (Fig.1). Among he
newly disco e ed na u al p oduc s, xylog ana umin A (2) comp ises an unp eceden ed B ing bea ing an oxygen
b idge be ween C-1 and C-8. He ein, we epo he isola ion, s uc u e elucida ion, and bioassay esul s o hese
compounds, as well as he plausible biosyn he ic pa hway o compound 2.
Resul s and Discussion
Isola ion and s uc u e elucida ion. The ai -d ied powde ed wigs and lea es (2.0 kg) o X. g ana um
we e pe cola ed ho oughly wi h MeOH a oom empe a u e. The concen a ed MeOH ex ac was pa i-
ioned be ween E OAc and H2O. The E OAc-soluble po ion was epea edly ch oma og aphed o a o d wel e
1S a e Key Labo a o y o D ug Resea ch, Shanghai Ins i u e o Ma e ia Medica, Chinese Academy o Sciences, Shanghai,
201203, China. 2Depa men o O ganic Chemis y, Uni e si y o Deb ecen, POB 20, 4010 Deb ecen, Hunga y.
3Syngen a Jealo ’s Hill In e na ional Resea ch Cen e, Be kshi e RG42 6EY, Uni ed Kingdom. 4Ins i u e o Biological
Science, Sun Ya -Sen Uni e si y, Xin Gang Wes Road 135, Guangzhou 510275, China. Co espondence and eques s o
ma e ials should be add essed o X.-W.L. (email: [email p o ec ed]) o Y.-W.G. (email: [email p o ec ed])
Recei ed: 07 July 2016
Accep ed: 02 Sep embe 2016
Published: 23 Sep embe 2016
OPEN
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Scien i ic RepoR s | 6:33908 | DOI: 10.1038/s ep33908
compounds. Fou known o hem we e eadily iden i ied by compa ison o hei spec oscopic da a wi h hose
epo ed in he li e a u e o be xylog ana in A (9)4, xyloca pin D (10)17, xyloca pin B (11)17, and xyloca pin G
(12) (Fig.1).17 On he basis o ca e ul analysis o NMR da a, and by compa ison wi h he known compounds,
he eigh new na u al p oduc s we e de e mined o be e ano i e penoids. Among hem, 1–6 all showed
cha ac e is ic signals o a α- u yl ing a C-17 posi ion, whe eas compound 7 possessed a γ-hyd oxybu enolide
g oup ins ead. A he same posi ion, while di e ed om 1–7, compound 8 exhibi ed a γ-bu y ol lac one moie y.
Acco dingly, he de ailed s uc u e elucida ion o hese new molecules is desc ibed as ollows.
9-epixylog ana in A (1) was isola ed as a colo less gum. The molecula o mula o 1 was de e mined o be
C34H42O12 by HRESIMS (m/z 665.2554 [M + Na ]+, calcd. 665.2574), co esponding o he molecula o mula
C34H42O12, which is he same as ha o he co-occu ing e ano i e penoid, xylog ana in A (9), p e iously iso-
la ed om he seeds o he same species.4 The NMR da a o 1 showed diagnos ic signals o a u an ing [δC 109.8,
119.7, 141.2, and 142.9; δH 6.34 (1H, d, J = 0.9 Hz), 7.41 (1H, s), and 7.41 (1H, , J = 0.9 Hz)], an α, β-unsa u a ed
lac one g oup (δC 117.7, 163.7, and 165.5; δH 6.12 s), and a e asubs i u ed double bond (δC 119.7, C-10 and 136.6,
C-1). De ailed analysis o 1D (Tables1 and 2) and 2D NMR (Fig.2) spec a e ealed ha he plana s uc u e o
1 was iden ical o ha o 9.4 In ac , he 13C NMR da a om C-3 o C-7 and C-16 o C-23 o 1 a e almos he same
as hose o 9, and he main di e ences a C-1, C-2, C-8, C-9, C-10, C-12, C-15 and C-30, indica ed he di e en
s e eochemis y be ween 1 and 9 in ce ain chi al cen e s. The ela i e con igu a ions o six s e eocen e s a C-2,
C-3, C-5, C-13, C-17, and C-30 we e elucida ed o be he same as hose o 9 by he compa ison o hei ROESY
spec al esul s, as well as by analysis o he coupling cons an s and spli ing pa e ns o H-2 (δH 3.30, dd, J = 11.1,
3.8 Hz), H-3 (δH 5.02, d, J = 3.8 Hz), and H-30 (δH 5.10, d, J = 11.1 Hz). NOE co ela ions obse ed o H-2/H-3,
H-2/CH3-28, H-3/CH3-28, and H-3/Ac-30 (Fig.2) sugges ed ha bo h H-2 and H-3 we e α-o ien ed. On he
con a y, he β-o ien a ion o H-5 and H-30 was de e mined by he signi ican NOE c oss-peak o H-5/H-30. The
coupling cons an s o H-2/H-3 (J = 3.8 Hz) and H-2/H-30 (J = 11.1 Hz) indica ed ha bo h H-2 and H-30 we e
axial o ien a ion, whe eas H-3 was equa o ial o ien a ion, which u he suppo ed he ela i e con igu a ions o
H-2, H-3, and H-30. The diagnos ic NOE co ela ions o H-30/H2-11 and H-30/H2-12 e ealed ha ings B and
C we e cis- used, and bo h 8-OH and 9-OH we e α-o ien ed. Thus, compound 1 was es ablished as 9-epime o
xylog ana in A (9).
Figu e 1. S uc u es o compounds 1–17.
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Scien i ic RepoR s | 6:33908 | DOI: 10.1038/s ep33908
Wi h he aim o de e mine he absolu e con igu a ion o 1, ime-dependen densi y unc ional heo y elec-
onic ci cula dich oism calcula ions (TDDFT-ECD) o i s solu ion con o me s we e ca ied ou . The ECD spec-
um o 1 was eco ded in ace oni ile (MeCN), which showed posi i e, nega i e and posi i e Co on e ec s (CEs)
a 270, 243 and 225 nm, espec i ely. The ini ial Me ck Molecula Fo ce Field (MMFF) con o ma ional analysis
o he a bi a ily chosen (2R, 3R, 5S, 8S, 9R, 13R, 17R, 30R) absolu e con igu a ion o 1 esul ed in 151 con o m-
e s, which we e e-op imized a B3LYP/6-31G(d) le el o heo y in acuo, as well as a B3LYP/TZVP le el wi h
Pola izable Con inuum Model (PCM) sol en model o MeCN. The gas-phase e-op imiza ion a o ded 9 con-
o me s wi h Bol zmann popula ion abo e 2%, while he PCM one yielded 14 geome ies abo e 2% (see S46 in
suppo ing in o ma ion). These s uc u es we e used as inpu o ECD calcula ions. The C-3 igloyl g oup is mo e
sui able o an axial o ien a ion in he low-ene gy con o me s (con o me s A-H), which is in acco dance wi h he
No. 1 2 3 4 5 6 7 8
11.37 m
23.30 dd (11.1, 3.8) 2.08 (3.5) 2.99 dd (11.6, 2.4) 3.64 dd (9.5, 2.7) 1.96 m
1.57 m
35.02 d (3.8) 5.52 d (3.5) 5.28 d (11.6) 5.06 d (9.5) 6.92 s 6.48 s 6.97 s 3.42 (2.8)
52.93 d (8.9) 2.24 m 3.15 s 3.38 dd (9.2, 2.3) 2.32 m 2.37 m 2.27 m 1.84 dd (12.9, 2.0)
62.38 dd (16.7, 3.3) 2.39 dd (16.4, 3.0) 5.30 s 2.36 m 2.32 m 2.49 d (14.3) 2.47 m 1.63 m
2.30 dd (16.7, 8.9) 2.17 m 1.77 m 2.46 m 2.31 m 2.27 m
82.24 m
92.19 m 2.15 m 2.02 m
10 1.97 m 2.40 m 2.37 m 2.27 m
11 2.19 m 2.10 m 2.05 m 2.01 m 1.79 m 2.37 m 3.10 dd (19.6, 7.2) 1.74 m
2.03 m 1.90 m 1.86 m 1.77 m 1.67 m 2.54 m 1.47 m
12 1.73 m 1.67 m 5.09 s 1.89 m 2.29 m 2.37 m 2.88 m 1.61 m
1.36 m 1.67 m 1.47 m 1.38 m 1.78 m 1.62 m 1.47 m
14 2.59 dd (12.7, 5.7) 2.40 d (8.6)
15 6.12 s 2.75 dd (16.5, 12.7) 3.35 d (19.4) 3.53 d (16.0) 6.28 s 6.68 s 6.17 s 5.23 dd (3.3, 1.5)
2.48 dd (16.5, 5.6) 2.65 dd (19.4, 8.6) 2.75 d (16.0)
16 2.11 dd (7.4, 3.4)
17 5.19 s 5.11 s 5.75 s 5.29 s 5.52 s 5.34 s 5.33 s 1.63 m
18 1.34 s 1.08 s 0.99 s 0.90 s 1.08 s 1.19 s 1.00 s 1.01 s
19 1.67 s 1.02 d (6.6) 1.14 s 1.08 s 1.15 d (5.7) 1.07 d (6.1) 1.04 d (5.6) 0.90 s
20 2.70 ddd
(13.8,10.4, 2.8)
21 7.41 s 7.41 s 7.46 s 7.61 s 7.61 s 7.52 s 4.46 (8.2)
3.91 (8.2)
22 6.34 d (0.9) 6.38 s 6.37 s 6.50 d (1.4) 6.50 b s 6.44 d (0.9) 7.42 s 2.51 dd (17.1, 7.9)
2.20 dd (17.1, 11.4)
23 7.41 (0.9) 7.43 d (1.5) 7.45 s 7.42 (1.4) 7.44 s 7.44 (1.5) 6.24 s
28 0.91 s 0.94 s 1.00 s 0.83 s 1.09 s 1.09 s 1.20 s 0.83 s
29 0.88 s 0.92 s 2.46 d (10.5) 1.14 s 1.18 s 1.11 s 0.85 s
2.26 d (10.5) 0.83 s
30 5.10 d (11.1) 5.30 d (3.5) 5.42 d (2.6) 3.51 d (2.7) 6.26 s 3.65 d (16.6) 6.49 s 1.09 s
3.45 d (16.6)
7-OMe 3.71 s 3.68 s 3.76 s 3.74 s 3.69 s 3.70 s 3.69 s
9-OMe 3.68 s
7-OAc 1.97 s
1-OAc 2.15 s
3-OAc 2.15 s 2.11 s
6-OAc 2.19 s
12-OAc 2.10 s
30-OAc 2.03 s 2.11 s 2.06 s 2.09 s
3′ 6.78 dd (7.2, 1.8) 7.02 m 6.78 q (6.8)
4′ 1.84 d (7.2) 1.86 d (7.0) 1.81 d (7.8)
5′ 1.84 s 1.92 s 1.77 s
8-OH 2.95 s 3.69 b s 3.83 s 3.94 s
9-OH 3.84 s 3.30 s
Table 1. 1H NMR spec oscopic da a o compounds 1–8a. aSpec a measu ed a 400 MHz in CDCl3.
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coupling cons an be ween H-2 and H-3 (3J2-Hax,3-Heq = 3.8 Hz). Ring B possesses a wis -boa con o ma ion wi h
equa o ial 30-OAc g oup in mos o he con o me s, which is in ag ee wi h he coupling cons an s be ween H-3
and H-30 (3J3-Hax,30-Hax = 11.1 Hz). As o p e en he side e ec s o he sol en , he ECD spec a we e also calcu-
la ed o he (2R, 3R, 5S, 8S, 9R, 13R, 17R, 30R) enan iome wi h a ious unc ions (B3LYP, BH&HLYP, PBE0) and
TZVP basis se o bo h he in acuo and he sol en model e-op imized s uc u es. The compu ed ECD cu es
o he indi idual con o me s we e qui e simila o each o he , and as well as o he expe imen al ECD spec um,
since hei ings D and E sha e he same o ien a ion. Mo eo e , all he Bol zmann-weigh ed ECD spec a ep o-
duced well he expe imen al ECD cu e wi h BH&HLYP/TZVP PCM/MeCN gi ing he mos ag eemen (Fig.3).
Thus, he absolu e con igu a ion o 1 was unambiguously de e mined as (2R, 3R, 5S, 8S, 9R, 13R, 17R, 30R). To
ou bes knowledge, his is he i s epo on he con igu a ional assignmen o limonoids wi h 9, 10-seco skele on
by TDDFT ECD calcula ions.
The ela ed xylog ana in A (9) was only epo ed o i s ela i e con igu a ion by he X- ay di ac ion analy-
sis4, while as i sha ed he same plana s uc u e as ha o 9-epixylog ana in A (1), he absolu e con igu a ion o 9
could hen be de e mined by compa ing hei ECD spec a, which ely upon he unsa u a ed δ-lac one and u an
ch omopho es o ing D go e ned by he C-13 and C-17 chi ali y cen e s. The simila ECD pa e n o 9 [225 nm
(Δ ε + 23.66), 269 nm (Δ ε + 1.57) in MeCN] and 1 indica ed he same (13R, 17R) absolu e con igu a ion o bo h
compounds. Thus he absolu e con igu a ion o xylog ana in A (9) can be deduced as (2R, 3R, 5S, 8S, 9S, 13R,
17R, 30R), which could u he allow he absolu e con igu a ional assignmen o he ela ed xylog ana ins B-D4.
The molecula o mula o xylog ana umin A (2), C31H40O12, was deduced by HRESIMS wi h ion peak a m/z
627.2431 [M + Na]+ (calcd 624.2417), sugges ing he p esence o wel e deg ees o unsa u a ion. In he 1H NMR
spec um, esonances a ising om se en me hyl g oups we e obse ed, including wo geminal (δ 0.92 and 0.94,
each 3H, s), one e minal (δ 1.08, 3 H, s), one seconda y (δ 1.02, 3H, d, J = 6.6 Hz), one me hoxyl (δ 3.68, 3H, s)
and wo ace yl g oups (δ 2.11 and 2.15, each 3H, s). Diagnos ic p o on signals ep esen a β- u an ing (δ 6.38,
7.41, and 7.43) was also ob ained. The 13C NMR spec um o 2 disclosed se en me hyl g oups, ou sp3 me h-
ylenes, h ee sp2 me hines, se en sp3 me hines, and en qua e na y ca bons ( ou ca bonyl g oups). Wi h ega d
o he 12 deg ee o unsa u a ion, and bea ing in mind he p esence o a u an ing and ou ca bonyl g oups,
xylog ana umin A (2) should possess i e o he ings.
The a o emen ioned da a implied ha compound 2 bo e a simila skele on as ha o compound 1. The
compa ison o he 1D and 2D NMR da a o 2 wi h hose o he co-occu ing limonoid 1 indica ed ha hey
sha ed he simila ings C, D, and E (Fig.4). Co espondingly, he cons uc ion o ings A and B was impo -
an o he s uc u e de e mina ion o 2. Two p o on-bea ing pa ial s uc u es o C-19 → C-10 → C-5 → C-6
and C-3 → C-2 → C-30 we e eadily ecognized om he 1H-1H COSY spec um (Fig.5). These wo s uc u al
segmen s we e connec ed o he qua e na y ca bons, C-1 and C-4, espec i ely, by he obse a ion o HMBC
co ela ions om Me-19 (δ 1.02, 3H, d, J = 6.6 Hz) o C-1/C-5, H-3 (δH 5.52, 1H, d, J = 3.5) o C-1/C-30, H-2 (δH
2.08, 1H, , J = 3.5) o C-1, Me-28 o C-4/C-5 and Me-29 o C-3/C-4. In addi ion, he HMBC co ela ions o OH-9
o C-9 and C-8, as well as he ypical hemike al chemical shi o C-9 (99.8), e ealed ha he hyd oxyl g oup (δH
3.30, OH-9) linked o C-9, which was u he connec ed o C-8. The me hoxyl g oup was loca ed a C-7 on he
basis o he HMBC c oss-peak om MeO- o C-7, and he assignmen o he wo ace oxyl g oups a C-3 and C-30
we e clea ly indica ed by HMBC co ela ions om H-3 (δ 5.52, 1 H, d, J = 3.5 Hz) o δC 169.8 and H-30 (δ 5.30, 1
H, d, J = 3.5 Hz) o δC 170.2 (Fig.4).
In e ms o ing B, he p esence o one ace al ca bon a δC 109.2 (C-1, sp3), one oxygena ed qua e na y ca bon
signal a δC 89.6 (C-8, sp3), a ypical hemiace al ca bon a δC 99.8 (C-9), and a e ia y oxygena ed ca bon a δC
71.3 (C-30) sugges ed ha ing B was cons uc ed ia he C-8 → C-30 → C-2 → C-1 → O → C-9 → C-8 bond o
o m a e ahyd opy an ing wi h an oxygen b idge be ween C-8 and C-1. The linkage o C-30 o C-8 was also
con i med by he dis inc HMBC co ela ion om H-30 o C-9. A plana s uc u e o 2 was hus p oposed as
depic ed in Fig.1, which was consis en wi h i s molecula composi ion and deg ees o unsa u a ion.
The ela i e con igu a ion o compound 2 was elucida ed by he analysis o ROESY spec um and p o on
coupling cons an s, as well as by analogy wi h ha o 1. The same ela i e s e eochemis y o C-2, C-3, C-5, C-13
and C-17 in 2 was deduced om he simila ca bon chemical shi s, p o on coupling cons an s, and ROESY
co ela ions wi h hose o 1 and he known compounds 10–16 ( o C-13 and C-17), as well as by a biogene ic
conside a ion o such limonoids in Na u e2,17. In addi ion, he NOE co ela ions be ween H-5 and CH3-19, H-10
and CH3-28, CH3-28 and H-3, H-3 and H-2, H-14 and CH3-18, H-14 and H-30, H-30 and OH-9 (Fig.4) u he
con i med he ela i e con igu a ion o 2R*, 3R*, 5S*, 9S*, 10R*, 13R*, 14R*, 17R*, 30S*. Al hough he ela i e
con igu a ions o C-1 and C-8 canno be de e mined by dis inc ROE co ela ions, he co ela ion be ween H-30
and OH-9 implied he β -o ien a ion o he oxygen b idge due o he smalle ansannula s ain.
Biogene ically, his in e es ing molecule migh be de i ed om hainang ana umin D (Fig.5), a limonoid
p e iously isola ed om X. g ana um wi h absolu e con igu a ion es ablished18, by a i s plausible weak acid p o-
mo ed nucleophilic addi ion o ace oxyl g oup a C-3 posi ion, which allowed he double bond mig a ion and he
epoxida ion om C-1 o C-9. The esul ing in e media e hen unde wen a C-1 hyd a ion, ollowed by a second
acid p omo ed epoxida ion om C-1 o C-8 wi h he elimina ion o H2O. Finally, a C-30 epime iza ion, which
possibly occu ed du ing he p e ious epoxida ion o lowe he ene gy o he molecule, allowed he p oduc ion
o compound 2. Since he ela i e s e eochemis y has been es ablished, he common biosyn he ic o igin o 2,
compound 1, he known compounds 9–16 and hainang ana umin D2,4,17,18, sugges ed he co esponding chi al
cen e s, especially C-13 and C-17 adjacen o he u an co e should be he same. The e o e, he absolu e con ig-
u a ion o compound 2 was deduced as (1S, 2R, 3R, 5S, 8S, 9S, 13R, 17R, 30S). Based on he abo e in o ma ion,
xylog ana umin A (2) was de e mined as a no el limonoid cha ac e ized by a 9, 10-seco skele on bea ing an
oxygen-b idge be ween C-1 and C-8 (Fig.1). and he disco e y o xylog ana umin A p o ided a new example o
he ex emely di e se and complex amily o limonoids.
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Scien i ic RepoR s | 6:33908 | DOI: 10.1038/s ep33908
6-O-ace yl xyloca pin D (3) ga e a HRESIMS pseudomolecula ion peak a m/z 769.2634 [M + Na]+, a plus
o 42 mass uni s on ha o he co-occu ing xyloca pin D (10), which was p e iously isola ed om he ui s o
X. g ana um wi h absolu e con igu a ion de e mined17, indica ing he p esence o an addi ional ace yl g oup in 3,
which was u he con i med by he ca e ul compa ison o hei 1H and 13C NMR da a (Tables1 and 2), wi h an
obse a ion o addi ional peaks o δH a 2.19 and δC a 169.6 and 21.0 on 3. The loca ion o he ace yl g oup a C-6
was es ablished by he expec ed down ield shi ed 1H NMR esonance o H-6 ( om δH 4.29 o 5.30). The e o e,
compound 3 was de e mined as he 6-ace yl de i a i e o xyloca pin D (10).
The HRMS da a o 14-hyd oxy-14,15-dihyd og ana umin C (4) displayed a pseudomolecula ion peak a
584.2643 [M]+ (calcd 584.2621), consis en wi h he molecula o mula C32H40O10. De ailed analysis o he 1H
and 13C NMR da a o 4 we e eminiscen o hose o 13, which was p e iously isola ed om he seeds o a K ishna
mang o e, X. g ana um19. Thei main di e ences we e an oxygena ed qua e na y ca bon a C-14 (δC 62.7) and a
No. 123456 7 8
1136.6 qC 109.2 qC 87.8 qC 214.5 qC 198.7 qC 199.3 qC 198.6 qC 32.6 CH2
236.2 CH 55.0 CH 46.3 CH 48.6 CH 130.4 qC 129.2 qC 128.4 qC 25.0 CH2
373.7 CH 76.3 CH 75.8 CH 77.1 CH 160.9 CH 158.3 CH 161.9 CH 75.9 CH
437.1 qC 39.4 qC 45.2 qC 39.4 qC 36.6 qC 36.8 qC 36.8 qC 36.9 qC
540.4 CH 41.7 CH 42.5 CH 42.4 CH 45.2 CH 43.0 CH 45.2 CH 41.8 CH
632.7 CH233.6 CH271.6 CH 33.3 CH234.8 CH234.7 CH234.6 CH223.2 CH2
7174.5 qC 174.0 qC 170.0 qC 174.1 qC 173.5 qC 173.6 qC 173.4 qC 75.3 CH
875.5 qC 89.6 qC 73.3 qC 62.7 qC 201.0 qC 197.8 qC 80.1 qC 42.2 qC
998.2 qC 99.8 qC 31.0 CH 54.4 CH 79.8 qC 172.8 qC 208.2/208.0 qC 43.0 CH
10 119.7 qC 36.5 CH 47.2 qC 48.2 qC 43.2 CH 45.6 CH 42.8 CH 37.4 qC
11 28.2 CH233.0 CH228.8 CH218.5 CH229.5 CH229.4 CH232.9 CH216.2 CH2
12 25.5 CH227.1 CH271.0 CH 33.1 CH228.6 CH229.8 CH225.6 CH233.8 CH2
13 38.3 qC 36.1 qC 39.3 qC 40.3 qC 41.5 qC 41.4 qC 38.6/38.5 qC 46.6 qC
14 163.7 qC 35.6 CH 46.4 CH 71.8 qC 156.6 qC 158.9 qC 162.5 qC 159.6 qC
15 117.7 CH 29.0 CH228.0 CH240.8 CH2121.2 CH 124.4 CH 117.7 CH 118.0 CH
16 165.5 qC 171.2 qC 169.7 qC 169.5 qC 163.4 qC 163.4 qC 164.5/164.3 qC 34.8 CH2
17 81.1 CH 79.4 CH 76.8 CH 78.4 CH 81.4 CH 78.5 CH 78.2/77.9 CH 58.1 CH
18 18.8 CH324.4 CH318.8 CH320.1 CH318.6 CH320.4 CH318.4/18.3 CH319.3 CH3
19 12.8 CH310.8 CH322.6 CH316.4 CH312.2 CH311.7 CH311.6 CH315.4 CH3
20 119.7 qC 120.9 qC 120.7 qC 120.1 qC 119.2 qC 119.6 qC 132.9 qC 37.5 CH
21 141.2 CH 140.8 CH 140.4 CH 141.2 CH 141.4 CH 141.6 CH 169.1/168.8 qC 72.6 CH2
22 109.8 CH 109.9 CH 109.1 CH 110.4 CH 109.7 CH 109.8 CH 150.4/149.7 CH 34.1 CH2
23 142.9 CH 143.3 CH 143.9 CH 142.9 CH 143.3 CH 143.4 CH 97.4/96.7 CH 176.8 qC
28 24.8 CH324.4 CH315.6 CH323.0 CH320.6 CH320.1 CH327.8 CH321.9 CH3
29 20.1 CH320.9 CH341.0 CH220.7 CH328.0 CH328.2 CH320.6 CH328.0 CH3
30 68.9 CH 71.3 CH 69.7 CH 62.8 CH 66.8 CH 41.3 CH267.8 CH 27.5 CH3
7-OMe 52.0 CH351.9 CH353.0 CH352.4 CH352.0 CH352.0 CH352.0 CH3
9-OMe 51.8 CH3
7-OAc 21.3 CH3
170.4 qC
1-OAc 21.0 CH3
168.4 qC
3-OAc 21.2 CH321.1 CH3
169.8 qC 169.4 qC
6-OAc 21.0 CH3
169.6 qC
12-OAc 22.1 CH3
169.7 qC
30-OAc 20.7 CH320.9 CH321.4 CH321.0 CH3
170.5 qC 170.2 qC 170.7 qC 169.9/169.8 qC
1′ 167.3 qC 167.0 qC 165.7 qC
2′ 128.7 qC 127.4 qC 127.8 qC
3′ 137.2 CH 140.4 CH 138.9 CH
4′ 14.5 CH314.8 CH314.6 CH3
5′ 12.1 CH312.3 CH312.0 CH3
Table 2. 13C NMR spec oscopic da a o compounds 1–8a. aSpec a measu ed a 100 MHz in CDCl3.

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Scien i ic RepoR s | 6:33908 | DOI: 10.1038/s ep33908
Figu e 2. Key 1H-1H COSY, HMBC, and ROESY co ela ions o 1.
Figu e 3. Expe imen al solu ion ECD spec um o 9-epixylog ana in A (1) and BH&HLYP/TZVP PCM/
MeCN calcula ed ECD spec um o (2R, 3R, 5S, 8R, 9S, 13R, 17R, 30R)-1 calcula ed o he low-ene gy
solu ion con o me s. Ba s ep esen he calcula ed o a ional s eng hs o he lowes -ene gy con o me .
Figu e 4. Key 1H-1H COSY, HMBC, and ROESY co ela ions o 2.
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Scien i ic RepoR s | 6:33908 | DOI: 10.1038/s ep33908
me hylene ca bon a C-15 (δC 40.8; δH 3.53, 1H, d, J = 16.0 Hz; 2.75, 1H, d, J = 16.0 Hz) in 4 in eplace o he Δ
14,15
double bond (δC 160.9 and 118.8) in 13. These da a indica ed ha he Δ
14,15 double bond was hyd a ed in 4, which
is in ull ag eemen wi h a plus o eigh een mass uni s o 4 on ha o 13. The HMBC co ela ions om H-15 o
C-14 and C-16, and CH3-18 o C-14 ga e u he suppo o he s uc u al assignmen o 4.
The ela i e con igu a ion o 4, excep C-14 posi ion, was de e mined o be he same as ha o 13 due o
he simila 13C NMR shi s and coupling cons an s in 1H NMR and u he con i med by ROESY expe imen s.
Un o una ely, he absence o he p o on signal o OH-14 in 4, which we e usually p esen ed in he NMR spec a
o he limonoids when measu ing in CDCl3, such as G anaxyloca pin C20, bea ing he simila subs uc u e as
compound 4, p e en ed us om assigning he con igu a ion o C-14 posi ion ia he a ailable NMR da a.
30-O- igloylhainang ana umin J (5) was isola ed as an op ically ac i e whi e amo phous powde . The
molecula o mula, C32H38O10, was es ablished by HRESIMS om he ion peak a 605.2346 [M+ Na ]+. I s 1H
and 13C NMR da a (Tables1 and 2) we e closely ela ed o hose o hainang ana umin J (14)18. The only di e -
ence was he eplacemen o he 30-O-isobu y yl g oup in 14 by a igloyl moie y (δH 6.78, q, J = 6.8 Hz, 1.80, d,
J = 6.8 Hz, and 1.77, s; δC 166.6 qC, 127.6 qC, 139.8 CH, 14.6 CH3, and 11.9 CH3) in 5. The e o e, he s uc u e o
30-O- igloylhainang ana umin J (5) was de e mined as shown in Fig.1.
The molecula o mula o 9-O-me hyl xylog ana in R (6), C28H34O9, was deduced by HRESIMS (m/z 537.2100,
calcd o [M+ Na]+ 537.2101). The 1H and 13C NMR spec a o 6 we e almos iden ical o hose o xylog ana in
R (15), which was isola ed as an an i eedan om he seeds o he same species wi h he absolu e con igu a ion
es ablished5, excep o he p esence o an addi ional me hoxy g oup (δH 3.68; δC 51.8), sugges ing ha 6 was an
O-me hyl de i a i e o 15, in ag eemen wi h an addi ion o 14 mass uni s in 6 o ha o 15. The chemical shi o
C-9 (δ 172.8) in 6 was up ield shi ed Δ δ 2.7 om ha o 15, indica ing he ca boxylic acid a C-9 was es e i ied o
me hyl es e , which was u he con i med by he HMBC co ela ion om 9-OCH3 (δH 3.67) o he ca bonyl ca -
bon a C-9 (δC 172.8). The comple e assignmen s o he 1H and 13C NMR o 6 we e achie ed by a comp ehensi e
analysis o 2D NMR spec a including HSQC, COSY, HMBC, and ROESY. Compound 6 was hus de e mined
as he me hyl es e o xylog ana in R (15). In iew o he p esence o me hyl es e moie y in a g ea numbe o
limonoids p e iously isola ed om his species, such as xylog ana ins A-D4, and hainang ana umins A-J18, he
au ho s belie e ha compound 6 is an o iginal na u al p oduc a he han an a i ac .
The molecula o mula o 30-O-ace ylhainang ana umin E (7) was es ablished as C29H34O12 by HRMS (m/z 597.1951,
calcd o [M+ Na]+ 597.1948). The γ-hyd oxybu enolide g oup was cha ac e ized by p o on signals a δH 7.42
(H-22) and 6.24 (H-23), and by ca bon signals a δC 132.9 (C-20), 169.1/168.8 (C-21), 150.4/149.7 (C-22), and
97.4/96.7 (C-23) in i s 1H and 13C NMR spec a (Tables1 and 2). The de ailed NMR da a analysis eminded us
hose o hainang ana umin E (16), p e iously isola ed om he seeds o Hainan mang o e X. g ana um18. The
only di e ences we e he p esence o he ace yl g oup (δH 2.09 s; δC 169.9/169.8 qC, 21.0 CH3) a C-30 in 7 ins ead
o he me hylbu y yl g oup in 16. In addi ion, wo se s o ca bon esonances a δ 208.2/208.0 (C-9), 38.6/38.5
Figu e 5. Plausible biosyn he ic pa hway o xylog ana umin A om hainang ana umin D.
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(C-13), 164.5/164.3 (C-16), 78.2/77.9 (C-17), 18.4/18.3 (C-18), 169.1/168.8 (C-21), 150.4/149.7 (C-22), 97.4/96.7
(C-23) in 13C NMR spec um sugges ed compound 7 was a mix u e o unsepa a ed C-23 epime s as depic ed in
Fig.1.
1,2-dihyd o-3α -hyd oxy- u anolide (8) was isola ed as a colo less gum. I s molecula o mula, C28H42O5,
was deduced by HREIMS a m/z 481.2892, a plus o wo mass uni s o ha o u anolide (17), p e iously iso-
la ed om he oo ba k o Tu aea obus a collec ed om Awasi, Kisumu Dis ic , Kenya21. The NMR spec a
o 8 we e simila o hose o 17, excep o he p esence o oxyme hine signal a C-3 (δH 3.42, , J = 2.8 Hz) in
1H NMR. A educ ion o he ke one a C-3 in 17 o he hyd oxyl g oup in 8 was hen easily ecognized, which
u he con i med by he up ield 13C NMR signal a 75.9 in 8 in eplace o ha a δ 216.2 in 17. In addi ion, he
α-o ien a ion o he hyd oxyl a C-3 o 8 was con i med by he ROESY co ela ions o H-3/CH3-29 and H-5/CH3-
28. The s uc u e o 1,2-dihyd o-3α -hyd oxy- u anolide (8) was hus de e mined as he C-3 educ i e de i a i e
o u anolide (17).
Simila as ha o compound 2, since he ela i e s e eochemis y o he new compounds 3, 5, 6, and 8 has been
es ablished, he common biosyn he ic o igin o such u an limonoids2,4,17,18 sugges ed he co esponding chi al
cen e s, such as C-13 and C-17 should be he same R con igu a ion. Thus he absolu e con igu a ion o he abo e
men ioned new compounds could be a bi a y de e mined as showed in Fig.1.
In summa y, eigh new e ano i e penoids (1–8) oge he wi h ou ela ed known compounds (9–12) we e
isola ed om he wigs and lea es o Chinese mang o e plan X. g ana um. The s uc u es o new compounds
we e elucida ed by ex ensi e spec oscopic analysis. The absolu e con igu a ion o 9-epixylog ana in A (1) was
de e mined by TDDFT ECD calcula ions, which inciden ally allowed he elucida ion o he absolu e con igu a-
ions o xylog ana in A (9) by compa ison wi h hei ECDs, sol ing a puzzle o he p e iously epo ed na u al
p oduc s. The disco e y o he 9, 10-seco limonoid 2 wi h a cha ac e is ic 2,7-dioxabicyclo [2.2.1]-hep ane ing
sys em added a no el skele on o he amily o e ano i e penoids, e ealing he high di e si y and complexi y
o such beau i ul molecules.
Neu op o ec i e ac i i y e alua ion. In he ligh o a wide ange o biological ac i i ies and pha maco-
logical p ope ies o limonoids2,8, we pe o med in i o in es iga ion o neu op o ec i e ac i i y o compounds
1–12 on PC12 cells, since he isola ed p o olimoloids by us om Toona cilia a a . pubescens displayed signi -
ican cell p o ec ing ac i i y11. Bo h compounds 11 and 12 showed mode a e neu op o ec i e e ec s agains
H2O2-induced neu o oxici y in PC12 cells a he concen a ion o 10 μM, wi h an inc ease in cell iabili y o
12.0% and 11.6%, espec i ely. N-Ace yl-L-cys eine (NAC) was used as he posi i e con ol wi h he inc ease in
cell iabili y o 22.0% a 10 μM. In compa ison wi h he es ed s uc u es, i is possible ha he a ia ion o ings
A and B o hese limonoids play an impo an ole o he neu op o ec i e ac i i y.
Me hods
Gene al expe imen al p ocedu es. Op ical o a ions we e measu ed on a Pe kin-Elme pola ime e
341. CD spec a we e ob ained on a JASCO 810 spec ome e . IR spec a we e eco ded on a Nicole -Magna
FT-IR750 spec ome e . The NMR spec a we e measu ed on B uke DRX 400 and Va ian Ino a 600 spec ome-
e s. Chemical shi s (δ) a e epo ed wi h he esidual CDCl3 (δH = 7.26 ppm) as he in e nal s anda ds o he 1H
NMR spec oscopy, and CDCl3 (δC = 77.0 ppm) o he 13C NMR spec oscopy. Chemical shi s we e exp essed in
δ (ppm) and coupling cons an s (J) in Hz. 1H and 13C NMR assignmen s we e suppo ed by 1H–1H COSY, HSQC,
HMBC and ROESY expe imen s. ESIMS and HRESIMS spec a we e eco ded on a Q-TOF Mic o LC-MS-MS
mass spec ome e . Re e sed-phase HPLC analysis was pe o med on an Agilen 1100 se ies liquid ch oma og a-
phy using a VWD G1314A de ec o a 210 nm and a semi-p epa a i e ZORBAX ODS column (250 mm × 9.4 mm
i.d., 5 mm pa icle size. Comme cial silica gel (Qing Dao Hai Yang Chemical G oup Co., 200–300 mesh) was used
o column ch oma og aphy (CC), and p ecoa ed silica gel pla es (Yan Tai Zi Fu Chemical G oup Co., G60 F-254)
we e used o analy ical TLC.
Plan ma e ials. The wigs and lea es o X. g ana um (2.0 kg) we e collec ed in Decembe 2009 om
Dongzhai Ha bo , Hainan p o ince, China, and iden i ied by P o esso Guo-Rong Xin o Ins i u e o Biological
Science, Sun Ya -Sen Uni e si y. A ouche specimen (NO. 09-P-69) is a ailable o inspec ion a he He ba ium
o Shanghai Ins i u e o Ma e ia Medica, Chinese Academy o Sciences.
Ex ac ion and isola ion. The ai -d ied powde ed wigs o X. g ana um we e pe cola ed wi h MeOH ( h ee
imes, each 7 days) a oom empe a u e. The ex ac was e apo a ed o d yness unde educed p essu e o gi e
154 g o esidue. The esidue was pa i ioned wi h E OAc o a o d 29.7 g E OAc ex ac . The E OAc ex ac was sep-
a a ed by Sephadex LH-20, MCI and silica gel column o ob ain i e ac ions (1–5). F .3 was subjec ed o silica gel
liquid ch oma og aphy, elu ing wi h CHCl3/MeOH ( om 100:1 o 8:2, g adien ), o ob ain 15 ac ions (3A-3O).
F ac ion 3C (65.3 mg) was ch oma og aphed on silica gel wi h pe oleum e he /ace one (8:2 o 1;1, g adien ) o
yield 7 (8.6 mg), and he sub- ac ion 3C1. Sub- ac ion 3C1 was pu i ied by HPLC (75:25) o a o d 5 (1.8 mg).
F ac ion 3D was sepa a ed by silica gel column wi h he eluen o pe oleum e he /ace one (8:2 o 7:3, g adien )
and subsequen ly pu i ied by semi-p epa a i e-HPLC elu ing wi h MeOH/H2O (70:30) o a o d 4 (2.1 mg) and
6 (2.3 mg). F ac ion 3E (2.17 g) was subjec ed o column ch oma og aphy on silica gel elu ed wi h a g adien o
pe oleum e he /ace one (9:1 o 1:1) o gi e nine majo ac ions 3E0–3E9. 3E7 was sepa a ed by silica gel column
elu ed wi h pe oleum e he /ace one (8:2 o 7:3) o a o d 12 (30.0 mg) and he sub- ac ion 3E7a, which was
pu i ied by e e sed phase HPLC (CH3CN/H2O, 67:33) o yield 8 (5.4 mg), while compounds 3 (1.0 mg) and 11
(4.8 mg) was p epa ed by column ch oma og aphy on silica gel elu ed wi h pe oleum e he /ace one (7:3) om
ac ion 3E9. F ac ions 3G was i s sepa a ed by column ch oma og aphy on silica gel elu ed wi h pe oleum
e he /ace one (8:2 o 6:4, g adien ) o gi e six sub- ac ions (3G1-3G6). 3G3 was pu i ied by e e sed phase
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HPLC elu ed wi h MeOH/H2O (80: 20) o yield 1 (1.5 mg). 3G4 was sepa a ed by e e sed phase HPLC (CH3CN/
H2O, 50:50), hen subjec ed o column ch oma og aphy on silica gen elu ed wi h pe oleum e he /ace one (8:2)
o gi e 2 (2.6 mg). F ac ions 3G5 and 3G6 we e sepa a ed by silica gel column ch oma og aphy wi h pe oleum
e he /ace one (70:30) and (65:25) o yield 9 (4.7 mg) and 10 (21.6 mg), espec i ely.
Chemical s uc u e da a. All in es iga ed compounds we e ≥ 95% pu e (HPLC, wa eleng h = 210 nm).
The NMR spec a o he compounds a e p o ided in he Suppo ing In o ma ion.
9-epixylog ana in A (1). Colo less gum,
α[ ]D
20
+ 48 (c 0.12, CH3CN); ECD (CH3CN) λmax (Δε): 270 (2.23), 243
(− 0.26), 225 (4.45), 206 (−1.53), 200sh (−1.43). IR (KB ) νmax 3432, 2924, 1725, 1381, 1261 cm−1; o 1H NMR
and 13C NMR spec oscopic da a, see Tables1 and 2; HREIMS m/z [M+ Na]+ 665.2554 (calcd. o C34H42O12Na,
665.2574).
Xylog ana umin A (2). Colo less gum,
α[ ]D
20
−15.0 (c 0.08, CH3CN); ECD (CH3CN) λmax (Δε): 254 (0.12), 235
(− 0.51), 212 (1.12). IR (KB ) νmax 3436, 2925, 1736, 1374, 1262, 1162, 1036 cm−1; o 1H NMR and 13C NMR
spec oscopic da a, see Tables1 and 2; HREIMS m/z [M+ Na]+ 627.2431 (calcd. o C34H42O12Na, 627.2417).
6-O-ace yl xyloca pin D (3). Whi e, amo phous powde , [α ]
D20
+ 4.3 (c 0.07, CH3CN); UV (MeOH) λmax
213 nm. IR (KB ) νmax 3426, 2924, 2853, 1741, 1373, 1234, 1041 cm−1; o 1H NMR and 13C NMR spec oscopic
da a, see Tables1 and 2; HREIMS m/z [M+ Na]+ 769.2634 (calcd. o C34H42O12Na, 769.2684).
14-Hyd oxy-14,15-dihyd og ana umin C (4). Whi e, amo phous powde ,
α[ ]D
20
+ 122.5 (c 0.04, MeOH); UV
(MeOH) λmax 212 nm. IR (KB ) νmax 3438, 2962, 1733, 1262, 1098, 1024, 802 cm−1; o 1H NMR and 13C NMR
spec oscopic da a, see Tables1 and 2; HREIMS m/z [M+ Na]+ 584.2643 (calcd. o C32H40O10Na, 584.2621).
30-O- igloylhainang ana umin J (5). Whi e, amo phous powde ,
α[ ]D
20
+ 22.2 (c 0.09, MeOH); UV (MeOH)
λmax 210 nm. IR (KB ) νmax 3439, 2962, 1735, 1671, 1383, 1260, 1166, 1026 cm−1; o 1H NMR and 13C NMR spec-
oscopic da a, see Tables1 and 2; HREIMS m/z [M+ Na]+ 605.2346 (calcd. o C32H40O10Na, 605.2343).
9-O-me hyl xylog ana in R (6). Whi e, amo phous powde ,
α[ ]D
20
+ 49.1 (c 0.05, MeOH); UV (MeOH) λmax
211 nm. IR (KB ) νmax 3432, 2919, 1735, 1630, 1091, 1046 cm−1; o 1H NMR and 13C NMR spec oscopic da a,
see Tables1 and 2; HREIMS m/z [M+ Na]+ 537.2100 (calcd. o C28H34O9Na, 537.2101).
30-O-ace ylhainang ana umin E (7). Colo less gum,
α[ ]D
20
+ 38.9 (c 0.19, MeOH); UV (MeOH) λmax 206 nm.
IR (KB ) νmax 3437, 2965, 1735, 1671, 1373, 1262, 1230, 1018 cm−1; o 1H NMR and 13C NMR spec oscopic da a,
see Tables1 and 2; HREIMS m/z [M+ Na]+ 597.1951 (calcd. o C29H34O12Na, 597.1948).
1,2-Dihyd o-3α -hyd oxy- u anolide (8). Colo less gum,
α[ ]D
20
− 17.6 (c 0.11, MeOH); IR (KB ) νmax 3437,
2923, 1782, 1726, 1378, 1259, 1033 cm−1; o 1H NMR and 13C NMR spec oscopic da a, see Tables1 and 2;
HREIMS m/z [M+ Na]+ 481.2892 (calcd. o C28H42O5Na, 481.2930).
Neu op o ec i e bioassay. The neu op o ec i e ac i i ies o compounds 1–12 agains hyd ogen pe oxide
(H2O2)-induced neu o oxici y in PC12 cells we e e alua ed by using he MTT me hod22, acco ding o he p o ocols
desc ibed in p e ious li e a u e.
Compu a ional sec ion. Mixed o sional/low mode con o ma ional sea ches we e ca ied ou by means o
he Mac omodel 9.7.223 so wa e23 using Me ck Molecula Fo ce Field (MMFF) wi h an implici sol en model
o chlo o o m. Reop imiza ions a B3LYP/6-31G(d) le el o heo y in acuo as well as B3LYP/TZVP wi h PCM
sol en model o MeCN we e ca ied ou ollowed by TDDFT-ECD calcula ions using a ious unc ionals
(B3LYP, BH&HLYP, PBE0) and TZVP basis se o he Gaussian 09 package24. Bol zmann dis ibu ions we e es i-
ma ed om he ZPVE co ec ed B3LYP ene gies in he gas-phase calcula ions and om he B3LYP ene gies in
he PCM ones. ECD spec a we e gene a ed as he sum o Gaussians25 wi h 2400 and 3000 cm−1 hal -heigh wid h
(co esponding o ca. 16 and 20 nm a 260 nm, espec i ely), using dipole- eloci y compu ed o a ional s eng hs.
The MOLEKEL so wa e package23 was used o isualiza ion o he esul s.
Re e ences
1. Shen, L.-R. e al. Chemical cons i uen s o plan s om he genus Xyloca pus. Chem. Biodi e s. 6, 1293–1308 (2009).
2. Ye, F. e al. Recen P og ess on he Mang o e Plan s: Chemis y and Bioac i i y. Cu . O g. Chem. 20, 1923–1942 (2016).
3. Wu, J. e al. Xyloccensins O and P, unique 8,9,30-ph agmalin o ho es e s om Xyloca pus g ana um. O g. Le . 6, 1841–1844 (2004).
4. Yin, S. e al. Xylog ana ins A-D: No el e ano i e penoids wi h an unusual 9,10-seco sca old om ma ine mang o e Xyloca pus
g ana um. O g. Le . 8, 4935–4938 (2006).
5. Wu, J. e al. Xylog ana ins F-R: an i eedan s om he Chinese mang o e, Xyloca pus g ana um, a new biogene ic pa hway o
e ano i e penoids. Chem. Eu . J. 14, 1129–1144 (2008).
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