Research Synopsis

Medicinal chemistry, bioactive natural products, new drug discovery and development, and Chinese medicine

K. H. Lee is the director of the Natural Products Research Laboratories and has discovered several thousand bioactive natural products and their synthetic analogs, providing leads for new generation drug design against AIDS, cancer, and other diseases, including many natural products and analogs currently in clinical trials or preclinical development.

Some of Lee's accomplishments:

• More than 740 research articles, 77 patents issued, 398 invited lectures and presentations
• Member of the editorial advisory board for 25 journals
• Numerous honors and awards including
  • Fellow of the American Association of Pharmaceutical Scientists
  • The Lifu Academic Award for Chinese Medicine, 1994
  • Fellow of American Association for the Advancement of Science, 1994
  • Academician, Academia Sinica, 1996
  • Outstanding Achievement Award, University of Minnesota at Minneapolis, 1999

  • Taiwanese-American Foundation Outstanding Achievement Award in Science and Engineering, USA, 2003

  • Kitasato Microbial Chemistry Medal, Japan, 2005
  • Norman R. Farnsworth Research Achievement Award from American Society of Pharmacognosy, 2009
  • Order of the Rising Sun, Gold Rays with Neck Ribbon, Government of Japan, 2011

Research Interests

The Natural Products Research Laboratories, under the direction of Dr. K.H. Lee, combines the fields of natural products and synthetic medicinal chemistry research to discover and develop bioactive natural products and their analogs as clinical trials drug candidates. Since 1971, the NPRL has discovered several thousand novel bioactive natural products and synthetic analogs. These discoveries are used as new leads to develop future pharmaceuticals agents in the same manner that numerous previously discovered bioactive natural products (including ephredrine, taxol, and artemisinin) were developed as current pharmaceutical agents to treat cancers and other diseases. Using basic natural products and medicinal chemistry principles coupled with modern technologies, including new computational techniques and mechanism of action or target-based and genomic evaluation methods, our newly discovered lead compounds will provide a solid foundation of potential chemotherapeutic drug candidates in the twenty-first century

Current research programs in the NPRL include the following:

1. Medicinal Chemistry
2. Bioactive Natural Products
3. New Anticancer and Anti-AIDS Drug Discovery and Development
4. Chinese Medicine

Highlights

The following example bioactive compounds discovered by the NPRL are currently in clinical trials or preclinical studies:

1. GL-331, a synthetic etoposide analog developed in the NPRL, was in Phase II clinical trial as an anticancer drug.
2. Bevirimat (PA-457, DSB, MPC-4326), a modified triterpene natural product, licensed previously to Panacos Pharmaceuticals, Inc. and now to Myriad Pharmaceutical Company, has succeeded in Phase IIa anti-AIDS clinical trials. Phase III clinical trials plan to begin in 2011, following the completion of Phase IIb clinical trials.  Bevirimat is a first-in-class maturation inhibitor.
3. Novel curcumin analogs discovered and developed in the NPRL were licensed to AndroScience Corporation of San Diego, CA. One compound, JC-9, is currently in a Phase II clinical trial for treating acne. JC-9 is planned for a clinical trial for prostate cancer in the near future.
4. A 2-phenyl-4-quinolone analog, CHM-2133-P, has shown excellent in vivo antitumor activity against ovarian cancer. Effpha Corp., Taiwan, has licensed this technology and is in process for initiating a Phase I clinical trial as an anticancer drug.
5. Preclinical studies on numerous novel promising natural product-based leads including DCP analogs as anti-AIDS agents as well as analogs of tylophorine and neotanshinlactone as drugs for treating lung and breast cancers are in progress.

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Ten Most Recent Publications

1. Antitumor agents 292. Design, synthesis and pharmacological study of S- and O-substituted 7-mercapto- or hydroxy-coumarins and chromones as potent cytotoxic agents. Chen Y, Liu HR, Liu HS, Cheng M, Xia P, Qian K, Wu PC, Lai CY, Xia Y, Yang ZY, Morris-Natschke SL, Lee KH. Eur J Med Chem. 2011 Dec 29. [Epub ahead of print] PMID: 22265685 [PubMed - as supplied by publisher]

2. 2-(3-Methoxyphenyl)-5-methyl-1,8-naphthyridin-4(1H)-one (HKL-1) induces G2/M arrest and mitotic catastrophe in human leukemia HL-60 cells. Hsu MH, Liu CY, Lin CM, Chen YJ, Chen CJ, Lin YF, Huang LJ, Lee KH, Kuo SC. Toxicol Appl Pharmacol. 2012 Jan 5. [Epub ahead of print] PMID: 22245593 [PubMed - as supplied by publisher]

3. Design, synthesis and cytotoxic activity of novel spin-labeled rotenone derivatives. Liu YQ, Ohkoshi E, Li LH, Yang L, Lee KH. Bioorg Med Chem Lett. 2012 Jan 15;22(2):920-3. Epub 2011 Dec 9. PMID: 22204911 [PubMed - in process]

4. Cancer preventive agents 11. Novel analogs of dimethyl dicarboxylate biphenyl as potent cancer chemopreventive agents(†). Hung HY, Nakagawa-Goto K, Tokuda H, Iida A, Suzuki N, Morris-Natschke SL, Lee KH. Pharm Biol. 2012 Jan;50(1):18-24. PMID: 22196579 [PubMed - in process]

5. Cytotoxic esterified diterpenoid alkaloid derivatives with increased selectivity against a drug-resistant cancer cell line. Wada K, Ohkoshi E, Morris-Natschke SL, Bastow KF, Lee KH. Bioorg Med Chem Lett. 2012 Jan 1;22(1):249-52. Epub 2011 Nov 11. PMID: 22142543 [PubMed - in process]

6. Picomolar dichotomous activity of gnidimacrin against HIV-1. Huang L, Ho P, Yu J, Zhu L, Lee KH, Chen CH. PLoS One. 2011;6(10):e26677. Epub 2011 Oct 24. PMID: 22039528 [PubMed - in process]

7. ortho-Quinone tanshinones directly inhibit telomerase through an oxidative mechanism mediated by hydrogen peroxide. Soares J, Keppler BR, Wang X, Lee KH, Jarstfer MB. Bioorg Med Chem Lett. 2011 Dec 15;21(24):7474-8. Epub 2011 Oct 8. PMID: 22044621 [PubMed - in process]

8. Structure-activity relationships of chalcone analogs as potential inhibitors of ADP- and collagen-induced platelet aggregation. Vijaya Bhaskar Reddy M, Tsai WJ, Qian K, Lee KH, Wu TS. Bioorg Med Chem. 2011 Dec 15;19(24):7711-9. Epub 2011 Aug 6. PMID: 22055718 [PubMed - in process]

9. Anti-AIDS agents 85. Design, synthesis, and evaluation of 1R,2R-dicamphanoyl-3,3-dimethyldihydropyrano-[2,3-c]xanthen-7(1H)-one (DCX) derivatives as novel anti-HIV agents. Zhou T, Shi Q, Chen CH, Huang L, Ho P, Morris-Natschke SL, Lee KH. Eur J Med Chem. 2012 Jan;47(1):86-96. Epub 2011 Oct 20. PMID: 22063755 [PubMed - in process]

10. Bis-chalcone analogues as potent NO production inhibitors and as cytotoxic agents. Vijaya Bhaskar Reddy M, Shen YC, Ohkoshi E, Bastow KF, Qian K, Lee KH, Wu TS. Eur J Med Chem. 2012 Jan;47(1):97-103. Epub 2011 Oct 20. PMID: 22115618 [PubMed - in process]