The principal objective of the program of research outlined herein is the development of general strategies and methods for the synthesis of complex natural products possessing cytotoxic, cocarcinogenic, and antileukemic activities. The development of concise ways to approach these diverse classes of compounds is required to permit systematic structural variation for testing structure-activity relationships and for acquiring new compounds for biological evaluation as clinical candidates. During the course of these studies, it will be necessary to extend the scope and limitations of select known reactions in utilitarian ways and to invent new ones. The synthetic approaches are designed to be adequately flexible and efficient so as to allow for all the intended applications. The targeted compounds are primarily comprised of medium-sized and/or strained ring systems. For example, the strained In,out-bicyclo[4.4.1]undecan-4-one substructure of ingenol is hopefully to be accessed by tandem [3.3] sigmatropy and WagnerMeerwein rearrangement. Seco-ent-kaurenes such as shikodomedin are to be constructed by applicability of methodology developed in a model study in which five of the six requisite steps are 100% stereocontrolled. The taxanes, members of which possess potent antitumor activity, are to be approached by a new strategy involving an anionic oxy-Cope rearrangement step followed by 1,2-shift of the gem-dimethyl substituted bridge. A totally new approach to the construction of oxygen-bridged sesquiterpenes such as zexbrevin is expected to facilitate rapid assembly of these complex molecules. Success in this area will allow for extension of our goals to the preparation of piptocarphin A and related oxagermacranolides. Our quest of the antileukemic agent jatrophatrione is to take the form of an incredibly short sequence based on anionic [3.3] sigmatropy. Synthetic entry to the highly oxygenated antitumor agents neoliacinic acid and pseudopterolide and their analogues shall rely on several interesting techniques for establishing their manifold stereogenic centers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA012115-21
Application #
3163606
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1977-06-01
Project End
1996-05-31
Budget Start
1991-06-01
Budget End
1992-05-31
Support Year
21
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Ohio State University
Department
Type
Schools of Arts and Sciences
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
Carter, Yvette M; Kunnimalaiyaan, Selvi; Chen, Herbert et al. (2014) Specific glycogen synthase kinase-3 inhibition reduces neuroendocrine markers and suppresses neuroblastoma cell growth. Cancer Biol Ther 15:510-5
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Carter, Yvette; Yeutter, Nicholas; Mazeh, Haggi (2014) Thyroglossal duct remnant carcinoma: beyond the Sistrunk procedure. Surg Oncol 23:161-6
Carter, Yvette; Sippel, Rebecca S; Chen, Herbert (2014) Hypothyroidism after a cancer diagnosis: etiology, diagnosis, complications, and management. Oncologist 19:34-43
Alhefdhi, Amal; Burke, Jocelyn F; Redlich, Aaron et al. (2013) Leflunomide suppresses growth in human medullary thyroid cancer cells. J Surg Res 185:212-6
Carter, Yvette; Roy, Madhuchhanda; Sippel, Rebecca S et al. (2012) Persistent hypertension after adrenalectomy for an aldosterone-producing adenoma: weight as a critical prognostic factor for aldosterone's lasting effect on the cardiac and vascular systems. J Surg Res 177:241-7
Xiao, Yuling; Jaskula-Sztul, Renata; Javadi, Alireza et al. (2012) Co-delivery of doxorubicin and siRNA using octreotide-conjugated gold nanorods for targeted neuroendocrine cancer therapy. Nanoscale 4:7185-93
Carter, Yvette M; Mazeh, Haggi; Sippel, Rebecca S et al. (2012) Safety and feasibility of laparoscopic resection for large (ýýý 6 CM) pheochromocytomas without suspected malignancy. Endocr Pract 18:720-6
Hou, Ningqi; Popkin, Barry M; Jacobs Jr, David R et al. (2011) Longitudinal trends in gasoline price and physical activity: the CARDIA study. Prev Med 52:365-9
Hou, Ningqi; Popkin, Barry M; Jacobs Jr, David R et al. (2010) Longitudinal associations between neighborhood-level street network with walking, bicycling, and jogging: the CARDIA study. Health Place 16:1206-15

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