1. Research Summary at Northeastern University
The O’Doherty lab
The use of de novo carbohydrate synthesis
for the SAR-study of SL0101
Sugyeom Kim
I finished bachelor’s degree majoring biochemistry at Northeastern University located in Boston. In
addition to doing Genetic research as a co-op at Broad Institute of MIT and Harvard, I had been working
in Prof. George O’Doherty’s lab on developing methods for the de novo synthesis of natural/unnatural
structures to discover diverse new biologically active natural product analogues. The project I was
working on adapts the techniques of asymmetric synthesis on the Structure Activity Relationship (SAR)
studies of anticancer natural product SL0101 (e.g., 2 and 3, Scheme 1) The big picture of this project
was to discover novel analogues with enhanced solubility, increased potency against breast cancer, and
improved selectivity towards the p90 ribosomal S6 kinase (RSK).
Scheme 1: O’Doherty approach to SL0101 SAR
The kinase RSK is one of the more promising cancer target as its increased expression has been
found in Triple Negative Breast Cancer (TNBC) cells. RSK-1 and RSK-2 facilitate breast cancer cell
growth and regulation. The inhibition of RSK1/2 has great potential for the treatment of cancer.
Forsteronia refracta is a plant, which is native to Central/South America. This organism contains a
natural product called SL0101 (1) that consists of two parts, an aglycone and sugar. SL0101 (1) is a
promising lead compound for human breast cancer because it selectively inhibits RSK-1 and RSK-2.
The issue associated with the use of SL0101 as a drug is its instability, which is due to the lability of the
anomer bond connecting the sugar to aglycone (e.g., acidic or enzymatic hydrolysis). This lability results
in reduced bioavailability in in vivo tests, which limits its ability to be used in breast cancer treatment.
Scheme 2: Mechanistic hypothesis for cyclitol cleavage of aglycone
To address this issue, the O’Doherty lab has been performed extensive SAR studies on SL0101 and
found a n-Proryl-cyclitol analogue (2) with significantly improved activity. While the cyclitols analogue
has shown significantly improved metabolic lifetimes, animal feeding studies have indicated that even
the cyclitol analogue has shown some degree of hydrolysis. Since this is unlikely to result from acid
catalyzed hydrolysis, the O’Doherty group has proposed an alternative oxidative mechanism by which
O
O
O
O
O
OHO
HO
OH
HO
O
Me
H
H
O
O
O
OMe
O
O
OHO
HO
OH
HO
O
SL0101 n-Pr cyclitol analogue
of SL0101
O'Doherty
SAR-studies
On going
SAR-studies
O
O
O
O
O
OHO
HO
X
HO
O
Me
H
H
A B
C
Next generation
SL0101 analogues
(X=H, F, Cl, or MeO)
A B
C
A B
C
1 2 3
O
O
O
O
O
OHO
HO
OH
HO
O
Me
H
H
n-Pr cyclitol analogue
of SL0101
Enzymatic
Oxidation
O
O
O
O
O
OHO
HO
O
HO
O
Me
H
H
H2O
O
O
OH
HO
OH
HO
OH
O
O
OHO
O
Me
H
H
+
Sugar group
of the analogue
A B
C
A B
C
A B
C
2
4
5 6
Aglycone group
of the analogue

2. this hydrolysis can occur (Scheme 2). In the proposed mechanism, they suggest the C-ring phenolic OH-
group is oxidized to a vinylogous quinone intermediate (4), which is then hydrolyzed to (5) and (6). We
hypothesize that C-ring substituted analogues that replace the OH-group (3, X = H, F, Cl, or OMe) may
have improved metabolic stability. My project was to synthesize these suitably protected aglycones (7),
which a graduate student, Yu Li will then use to synthesize the corresponding SL0101 analogues (3). In
addition, I would prepare the unprotected aglycones (9), which would be used in anti-cancer, and
metabolic stability studies, by our collaborator Prof. Deb Lannigan. (Scheme 4)
Scheme 3: My project’s target compounds to explore the aglycone SAR of SL0101
The protected aglycones (7) were being synthesized via the route outlined in Scheme 4. The route
was based upon our previously established route to the SL0101 aglycon, where the A ring hydroxyl
groups are protected as Bn-ethers. The key difference in this new route is that the C-ring OBn group is
replaced with our proposed substitutents (X = H, F, Cl, or OMe), which we hypothesize will be potential
factor that could improve bioavailability. We have completed the synthesis for the aglycone with an
OBn group and are close to synthesizing the chloro-compound. In the near future we hope to finish the
synthesis of the remaining analogues (X = H, F, and OMe) and begin to test our hypothesized effect of
C-ring substitution on anticancer activity, RSK inhibition and metabolic stability.
Scheme 4: My project’s synthetic approach to new SL0101 aglycones
O
O
O
O
O
OHO
HO
X
HO
O
Me
H
H
A B
C
A new analogue of SL0101
O
O
OH
HO
X
HO
O
O
OH
BnO
X
OBn
(X = H, F, Cl, or OMe)
(X = OH, H, F, Cl, or OMe)
OpNO2Bz
O
O
Me
H
H
+
Yu Li's project Sugyeom Kim's project
New SL0101 aglycone
analogues for screening3
7
(X = OBn, H, F, Cl, or OMe)
8
9
A B
C
A B
C
OH
OH
HO
Br
OH
OBn
BnO
O
K2CO3
DMF
40%
COOH
X
EDCI/DMAP
BnO
OBn
O
O
O
X
Br
DCM
70%
BzOK, ACN
reflux
55%
BnO
OBn
O
O
O
X
OBz
BnO
OBn
O
O
OH
X
1. NaH, THF, Reflux
2. AcOH, NaOAc
3. 5% NaOMe,
MeOH/DCM
70%
OH
OH
HO
O
Ac2O
BF3•Et2O
2 d
75%
1. PTT 2.5 eq
THF
2. (EtO)2POH
Et3N, THF
BnO
OBn
O
O
O
X
A B
C
Aglycone Group Analogue
of SL0101 (protected)
(X = H, F, Cl, or MeO)
95%
HO
OH
O
O
OH
X
A B
C
Aglycone Group Analogue
of SL0101 (unprotected)
(X = H, F, Cl, or MeO)
BnO
OBn
O
O
OH
X
H2
Pd/C
10 11 12 13
14 15
7
9
7
Reagent: PTT = (CH3)3NPh(Br3)