Y OUNG I NNOVATORS 2009 Structural Simplification of Neo-tanshinlactone — Discovery of Potent and...
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YOUNG INNOVATORS 2009 Structural Simplification of Neo- tanshinlactone — Discovery of Potent and Selective Anti-Breast Cancer Agents Yizhou Dong, Ph. D. The University of North Carolina at Chapel Hill
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Transcript of Y OUNG I NNOVATORS 2009 Structural Simplification of Neo-tanshinlactone — Discovery of Potent and...
YOUNG INNOVATORS 2009Structural Simplification of Neo-tanshinlactone
— Discovery of Potent and Selective Anti-Breast Cancer Agents
Yizhou Dong, Ph. D.The University of North Carolina at Chapel Hill
Young Innovators 2009
ABSTRACT
• Neo-tanshinlactone (1) is a potent and selective anti-breast cancer agent. In a continuing study, we explored how the individual rings in the molecule influence the in vitro anti-breast cancer activity. The results led to the discovery of a novel class of anti-breast cancer agents, 2-(furan-2-yl) naphthalen-1-ol derivatives, based on an active C-ring opened model compound 7. Further optimization led to 20 and 21 as new anti-breast cancer agents with better selectivity than neo-tanshinlactone analog 2. Interestingly, compound 26 showed broad in vitro cytotoxicity against human cancer cell lines.
Young Innovators 2009
CANCER — LEADING CAUSE OF DEATH
Cancer will overtake heart disease as the world’s number one killer by 2010. 27 million new cancer cases by 2030.$960.7 billion in 2000 $1.472 trillion in 2020Breast cancer: the 2nd leading cause of cancer deaths in womenLife time risk: 5% in 1940 12.3% in 2008
HealthDay News
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CANCER — LEADING CAUSE OF DEATH
• Breast cancer is the most common cancer among women. According to the American Cancer Society, the disease accounts for more than one quarter of cancers diagnosed in US women. Toxic side effects, low tumor selectivity, and multidrug resistance with cancer chemotherapy prompt us to develop novel potent anti-breast cancer agents.
Young Innovators 2009
NEO-TANSHINLACTONE: AN ANTI-BREAST CANCER NATURAL PRODUCT
• Selective cytotoxicity against two estrogen receptor positive (ER+) breast cancer cell lines MCF-7 and ZR-75-1. In postmenopausal women, more than 60% of breast cancers are ER+.
• Potent activity against estrogen receptor negative HER2 over-expression positive (ER-, HER2+) breast cancer cell line SK-BR-3.
• Issues: low water solubility and hard to optimize
O
O
O
CH3
R
1: R = Me (Neo-tanshinlactone)
2: R = Et (More potent analog)
Young Innovators 2009
RATIONAL DESIGN
original scaffold
O
O
OA B
C D
O
O
O
OR
scaffold 1
HOOC
OH
O
Rscaffold 2
R'O
O
Rscaffold 3
O
O
OR
scaffold 4
1
2
3
4
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SYNTHETIC PATHWAY TO SCAFFOLDS 1 & 2
(a) HOAc, NH4OAc, chloroacetone, toluene, EtOH, reflux; (b) BBr3, DCM, 50 C; (c)
Cs2CO3, DMF, acetone, 50 C; (d) 5% NaOH (aq), reflux.
O
O
O
HO
O
O
OH
O
O
O
O
O
15 3 4
a b
O
O
O
RO
c
5: R= iPr
6: R= hexyl
d
O
O
O
OH
O
HOOC
16 7
Young Innovators 2009
SYNTHETIC PATHWAY TO SCAFFOLDS 3 & 4
Br Me
OO
11: R= H R'=
12: R= H R'=
O
Me
8: R= H R'=
9: R= Me R'=
10: R= H R'=
O
17, 18
R2O
O
R1
OH
R1
R2COCl
O
O
R
O
O N
S
13: R=
14: R=
19
O
O
OHa or b
(a) 3-bromoprop-1-yne, K2CO3, acetone, reflux, 40%; (b) NMP, DABCO, dimethylcarbamothioic chloride, 50 C, 85%.
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ANTI-BREAST CANCER ACTIVITY— SCAFFOLDS 1 & 2
cmpd scaffold R MCF7 SK-BR-31 -- -- 0.6 0.23 1 Me >20 10.54 1 H >20 7.85 1 i-Pr 12.0 10.86 1 Hexyl >20 15.97 2 H 6.0 7.0
HOOC
OH
O
R scaffold 2
mean ED50 (µg/mL), Standard error of
independent determinations was less than 5%
O
O
O
OR
scaffold 1
O
O
O
1
Young Innovators 2009
ANTI-BREAST CANCER ACTIVITY— SCAFFOLD 3
cmpd scaffold R R’ MCF7 SK-BR-3
8 3 H >20 >20
9 3 Me >20 >20
10 3 H 11.0 >20
11 3 H 15.5 >20
12 3 H >20 >20
R'O
O
R
mean ED50 (µg/mL), Standard error of
independent determinations was less than 5%
O
O
Me
Br Me
OO
Young Innovators 2009
ANTI-BREAST CANCER ACTIVITY— SCAFFOLD 4
cmpd scaffold RMCF7(ER+)
SK-BR-3 (HER2+)
13 4 >20 17.9
14 4 15.5 10.9
O
O
OR
mean ED50 (µg/mL), Standard error of
independent determinations was less than 5%
N
S
2
7
5
13
9
H-bond
CONFORMATIONAL SEARCH & PHARMACOPHORE ANALYSIS
PCH annotation
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Young Innovators 2009
CONTRIBUTION OF INDIVIDUAL RINGS A-D
O
O
OCritical
Critical
Can be opened
Young Innovators 2009
ANALOG DESIGN
7
HOOC
OH
O
scaffold 2
R5
R4
O
R2
R1
R3
20: R4= OH, R5= COOH24: R4= OMe, R5= COOH26: R4= OMe, R5= COOMe
R1 R2 R3 R4 R5 MCF-7 SK-BR-3
TAM 5 5
7 H Me H OH COOH 6 7.0
20 Et Me H OH COOH 3.3 1.0
21 OMe Me H OH COOH >20 3.5
22 OEt Me H OH COOH 7.5 6.0
23 H Me H OMe COOH 18 16.7
24 Et Me H OMe COOH 4.3 8.5
25 H Me H OMe COOMe 8.5 6.5
26 Et Me H OMe COOMe 2.5 1.2
27 H Me H OH CH2OH 7 9.5
28 Et Me H OH CH2OH 12 12.8
29 Et Me H OMe CH2OH -- 0.8
30 Et Me Me OH COOH 8.5 10.4
31 Et Et H OH COOH 5.1 5.4
MeOOC
OMe
O
Et
26
HOOC
OH
O
Et
20
ANTI-BREAST CANCER ACTIVITY
HOOC
OMe
O
Et
24
Young Innovators 2009
TAM: tamoxifen; mean ED50 (µg/mL), Standard error of
independent determinations was less than 5%
R1 R2 R3 R4 R5 MCF-7 SK-BR-3
TAM 5 5
7 H Me H OH COOH 6 7.0
20 Et Me H OH COOH 3.3 1.0
21 OMe Me H OH COOH >20 3.5
22 OEt Me H OH COOH 7.5 6.0
23 H Me H OMe COOH 18 16.7
24 Et Me H OMe COOH 4.3 8.5
25 H Me H OMe COOMe 8.5 6.5
26 Et Me H OMe COOMe 2.5 1.2
27 H Me H OH CH2OH 7 9.5
28 Et Me H OH CH2OH 12 12.8
29 Et Me H OMe CH2OH -- 0.8
30 Et Me Me OH COOH 8.5 10.4
31 Et Et H OH COOH 5.1 5.4
HOOC
OH
O
Et
20
ANTI-BREAST CANCER ACTIVITY
HOOC
OH
O
OMe
21
Young Innovators 2009
mean ED50 (µg/mL), Standard error of
independent determinations was less than 5%
R1 R2 R3 R4 R5 MCF-7 SK-BR-3
TAM 5 57 H Me H OH COOH 6 7.0
20 Et Me H OH COOH 3.3 1.021 OMe Me H OH COOH >20 3.522 OEt Me H OH COOH 7.5 6.023 H Me H OMe COOH 18 16.724 Et Me H OMe COOH 4.3 8.525 H Me H OMe COOMe 8.5 6.526 Et Me H OMe COOMe 2.5 1.227 H Me H OH CH2OH 7 9.528 Et Me H OH CH2OH 12 12.829 Et Me H OMe CH2OH -- 0.830 Et Me Me OH COOH 8.5 10.431 Et Et H OH COOH 5.1 5.4
HOH2C
OMe
O
Et
29
ANTI-BREAST CANCER ACTIVITY
HOOC
OH
O
Et
20
Young Innovators 2009
mean ED50 (µg/mL), Standard error of
independent determinations was less than 5%
cmpd MCF-7 SK-BR-3 ZR-75-1 MDA-MB-231 A549 DU145 KB KB-vin
2 0.2 0.1 0.1 >10 10.6 15.9 13.1 13.2
20 3.3 1.0 0.3 >10 10.6 8.7 9.1 7.0
21 >20 3.5 0.6 >10 10.1 8.2 9.7 8.9
26 2.5 1.2 1.3 2.3 1.5 2.2 1.7 1.3
29 -- 0.8 6.5 9.1 9.6 7.2 7.0 6.6
DIFFERENT TUMOR-TISSUE-TYPE SELECTIVITY
HOOC
OH
O
Et
20
HOOC
OH
O
OMe
21
MeOOC
OMe
O
Et
26
HOH2C
OMe
O
Et
29
Young Innovators 2009
mean ED50 (µg/mL), Standard error of
independent determinations was less than 5%
HOOC
OH
O
Et20
MeOOC
OMe
O
Et26
DIHEDRAL ENERGY ANALYSES
Hydrogen bond ‘locks’ the conformation
H-bond
Narrow shape implies less flexible & difficult to vary
Broader shape implies more flexible
Energy(kcal/mol)
Young Innovators 2009
O
O
O
32
different antitumor selectivity
OH
O
Et
HOOC
20
FURTHER DESIGN OF TNO DERIVATIVES
tetrahydronaphthalene-1-ol (TNO) derivatives
Young Innovators 2009
OH
O
HOOC
R
Young Innovators 2009
CONCLUSION
O
O
O
OR
scaffold 1
R'O
O
R
scaffold 3
O
O
OR
scaffold 4
HOOC
OH
O
R
scaffold 2
O
O
O
CH3
R1
H
Neo-tanshinlactone
Young Innovators 2009
CONCLUSION
R2
O
CH3
R1
R3
20: R1= Et; ZR-75-1/MCF-7 >1021: R1= OMe; ZR-75-1/MCF-7 >302: ZR-75-1/MCF-7 =2
H
optimal combination
20, R2= OH, R3= COOH selective anti-breast cancer 29, R2= OMe, R3= CH2OH, highly selective for SK-BR-326, R2= OMe, R3= COOMe, active against all cell lines tested
Young Innovators 2009
ACKNOWLEDGMENTS
• Dr. Kuo-Hsiung Lee
• Dr. Qian Shi
• Dr. Ken Bastow
• Dr. Arnold Brossi
• Dr. Susan Morris-Natschke
• Dr. Kyoko Goto
• Dr. Simon Wang
• Yi-Nan Liu
• Pei-Chi Wu
National Cancer Institute, NIH, CA-17625
Young Innovators 2009
REFERENCES
1. Wang, Bastow, Sun, Lin, Yu, Don, Wu, Nakamura, and Lee, J. Med. Chem., 47, 5186 (2004).
2. Wang, Nakagawa-Goto, Bastow, Don, Lin, Wu, Lee, J. Med. Chem., 49, 5631 (2006).
3. Dong, Shi, Liu, Wang, Bastow, and Lee. J. Med. Chem., 52, 3586 (2009).4. Dong, Shi, Nakagawa-Goto, Wu, Bastow, Morris-Natschke, Lee, Bioorg. Med.
Chem. Lett., 19, 6289 (2009). 5. Dong, Shi, Nakagawa-Goto, Wu, Morris-Natschke, Brossi, Bastow, Lee,
Bioorg. Med. Chem., submitted.6. Dong, Shi, Pai, Peng, Pan, Teng, Nakagawa-Goto, Yu, Liu, Wu, Bastow,
Morris-Natschke, Brossi, Lang, Hsu, Hung, Lee, and Lee, J. Med. Chem., submitted.
7. Lee. Dong, Shi, and Bastow, U.S. Provisional Patent Application No. 61/139,208
8. Lee, Dong, Shi, Bastow, and Wu, U.S. Provisional Patent application No. 61/139,241.
9. Lee, Dong, Shi, Bastow, U.S. Provisional Patent application No. 61/243,731
Young Innovators 2009
YIZHOU DONG
• Ph.D. University of North Carolina at Chapel Hill, August 2009
in Pharmaceutical Sciences, • M.S. Shanghai Institute of Organic Chemistry, July 2005
in Organic Chemistry, • B.S. Peking University, July 2002
in Pharmaceutical Sciences,
My current research focuses on discovery and development of novel anti-cancer agents, especially breast cancer. Two companies, Calvert Research Institute and Bayer Schering Phama, have shown great interest in our inventions and are working to license our anti-breast cancer agents.
Email: [email protected]
