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Organic Drug Development
Biochemistry Chemistry Research at UCF
The main goal of this research is to discover new drugs leads with potential for development as new pharmaceutical agents for the treatment of breast cancer, colon cancer, leukemia, myeloma (bone cancer), tuberculosis, and blood diseases. These new drugs leads can be discovered through the synthesis of novel compounds or through the isolation of new compounds from natural products. Currently we are involved in a collaborative effort with Professor Olga P. Kransykh of Perm State University (PSU) in Perm, Russia relative to the synthesis of novel new heterocyclic molecules. These novel compounds are then evaluated for their toxicity in mice with a pharmacologist at PSU (Professor Sergey Solodnikov). Those compounds with low toxicity are tested for activity against various disease targets in collaboration with molecular biologists at UCF (Dr. Saleh Naser-TB), USF-Moffitt Cancer Center (Dr. Said Sebti) and the Health Research Institute of the Orlando Regional Healthcare System (Dr. David Flory-breast cancer). Finally, if a novel compound has shown low toxicity and high activity then an attempt is made to elucidate the complete mechanism of action. A total of 6 US patents have already been issued on this work.
They are:
See frames 1-5 below for illustrated compounds of interest and patents that have been issued.
Breast Cancer
Figure 1 |
Figure 1. Compound with 100% activity against breast cancer and low toxicity in mice: Methyl 2-(N'-fluoren-9-ylidenehydrazino)-5,5-dimethyl-4-oxobutanoate
References:
- Miles, D. Howard; Solonikov, Sergey Yurjevich; Krasnykh, Olga Petrovna; Pimenova, Elena Valentinovna; Goun, Elena A. "Treatment of Breast Cancer." 2003 Patent No. US 6,638,975 B1.
- Mile, D. Howard; Solodnikov, Sergey Yurjevich; Krasnykh, Olga Petrovna; Pimenova, Elena Valentinovna; Goun, Elena A. "Treatment of Breast Cancer." 2003 Patent No. US 6,602,907 B1
Colon Cancer and Leukemia
Figure 2 |
Figure 2. Synthetic Route to a Novel Compound with activity against Leukemia and Colon Cancer: Methyl 4-(4-ethoxyphenyl)-2-(N'-fluoren-9-ylidenehydrazino)-2-hydroxy-4-oxobutanoate
Myeloma (Bone Cancer)
Figure 3 |
Figure 3. Compound with 100% activity against Myeloma (bone cancer) and low toxicity in mice: Methyl 4-(4-chlorophenyl)-2-(N'-fluoren-9-ylidenehydrazino-4-oxo-2-butenoate)
Reference:
- D. Howard Miles, Solodnikov Sergey Yurjevich, Krasnykh Olga Petrovna, Korotkova Tatiana Alexandrovna, and Elena A. Goun. "Treatment of Myeloma." Feb. 3, 2004, Patent No. US 6,686,496 B1.
Tuberculosis
Figure 4 |
Figure 4. Compound with 100% activity against Mycobacterium Tuberculosis and low toxicity in mice: 4-benzoyl-3-benzoyloxy-2-(2-oxo-2H-1,4-benoxazin-3-yl) pyrido [2,1-c][1,4] benzoazin-1,5-dione
References:
- D. Howard Miles, Krasnykh Olga Petrovna, Saleh Naser, Solodnikov Sergey Yurjevich, Elena A. Goun, and Suslonov Vladimir Michailovich. "Methyl Esters of Substituted 4-oxo-2-butenoic acid for Treatment of Tuberculosis." Jan. 27, 2004, Patent No. US 6,683,110 B1.
- Miles, D. Howard; Krasnykh, Olga Petrovna; Saleh, Naser; Solodnikov, Sergey Yurjevich; Goun, Elena A.; Suslonov, Vladimir Michailovich. "2-Oxo-1,4-benzoxazine Compounds for Treatment of Tuberculosis." 2003, Patent No. US 6,649,610 B1.
Blood Diseases (Anticoagulants)
Figure 5 |
Figure 5. Antithrombin: 4-ethoxybenzoyl-3,5-dihydroxy-1-diphenylmethyleneamino-5-methoxycarbonyl-2,5-dihydro-2-pyrrolone
References:
- Goun, E.; Cunningham, G.; Solodnikov, S.; Krasnykch, O.; Miles, D.H. "Isolation and evaluation of the Antithrombin and Anticancer Activity of Three Compounds from Origanum vulgare." Fitoterapia, 2002, 73, 692-694.
- Goun, Elena A.; Petrichenko, V.M.; Solodnikov, S.U.; Suhinina, T.V.; Kline, Martin A.; Cunningham, Glenn; Nguyen, Chi; Miles, Howard. "Anticancer and Antithrombin Activity of Russian Plants." Journal of Ethnopharmacology, 2002, 81, 337-342.
- Chistokhodova, Natalya; Nguyen, Chi; Calvino, Tony; Kachirskaia, Ioulia; Cunningham, Glenn; Miles; D. Howard. "Antithrombin Activity of Medicinal Plants from Central Florida." Journal of Ethnopharmacology, 2002, 81, 277-280.
Synthesis of Natural Products
Figure 6 |
In regard to the isolation of new drug leads from natural plant products, plants are collected in collaboration with local faculty members in the Department of Botany at universities in the Azores, Florida, Indonesia, Philippines, Russia, Thailand, and Vietnam, The plants are then extracted with hexane and then methanol to yield a relatively nonpolar and relatively polar fractions. These fractions are then screened for activity against the disease targets previously mentioned. The fractions that are active are then chromatographed repetitively until a pure active compound is isolated. The structure of the compound is then elucidated. If a compound is extremely promising it is prepared synthetically and then use for mechanism of action studies. The justification for this work is the fact that natural products remain, to this day, the most abundant source of new pharmaceuticals. See frames 6 and 7 which illustrate the total synthesis of the fish toxin 5-0-metylembelin that was isolated from a mangrove tree of the Philippines.
Figure 6. Total Synthesis of the Novel Fish Toxin 5-0-Methylembelin
Reference:
- Miles, D. Howard and Matthew Payne. "Synthesis of 5-O-methylembelin." Tetrahedron, 2001, 57, 5769-5772.
Isolation and Structure Elucidation of Novel Biological Active Natural Products
Figure 7 |
Figure 7. Novel anticancer Juncosol from Juncus roemenanus and the novel fish toxin Vallapin from Heritiera littoralis
A third phase of our research is to sythesize novel highly conjugated heterocyclics attempt that may process optical properties. Figure 8 gives the structure of a novel synthetic compound that is being investigated for potential optical properties in collaboration with Dr. Kevin Belfield. The symmetry, complete conjugation, and the presence of heteroatoms (sulfur, nitrogen, and oxygen) contained in this molecule provide a system that is of interest for study relative to possible optical properties
Figure 8 |
Figure 8. A Compound Synthesized by Faculty Partners at Perm State Univ. in Perm, Russia
References:
- D. H. Miles, J. Bhattacharyya, N. V. Mody, J. L. Atwood, S. Black, and P. A. Hedin. "The Structure of Juncusol: A Novel Cytotoxic Dihydrophenanthrene from the Estuarine Marsh Plant Juncus roemenanus." Journal of the American Chemical Society, 1977, 99, 618.
- D.H. Miles, D.S. Lho, V. Chittawong, A.A. de la Cruz, and E.D. Gomez, J.A. Weeks and J.L. Atwood. "Toxicants from the Mangrove Plant VII: Vallapin and Vallapianin, Novel Sequiterpene Lactones from the Mangrove Plant Heritiera littoralis." The Journal of Natural Products Chemistry, 1991, 54(1), 286.
For More Information
D. Howard Miles
Department of Chemistry, CH 117
University of Central Florida
Orlando, FL 32816
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