Aza-epoxy-guaiane derivatives and treatment of cancer
Inventors
Chain, William J. • Beutler, John A. • Fash, David • Figg, William D. • Li, Zhenwu • Peer, Cody John • Ramos, Joe William • Sulzmaier, Florian J.
Assignees
University of Hawaii at Hilo • US Department of Health and Human Services
Publication Number
US-9676788-B2
Publication Date
2017-06-13
Expiration Date
2035-02-05
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Abstract
Disclosed is a compound of formula (I) or formula (II): (Formulas should be inserted here) wherein R1-R6 are as defined herein. Also disclosed are a pharmaceutical composition comprising such a compound and a method of treating or preventing cancer in a mammal in need thereof, comprising administering to the mammal a compound of formula (I) or formula (II).
Core Innovation
The invention provides aza-epoxy guaiane derivatives of formula (I) or formula (II), including epimers thereof, characterized by specific substituents R1 through R6 as defined. These compounds and their pharmaceutical compositions are applied for treating or preventing cancer in mammals by administering an effective amount of such compounds. The compounds are noted for oral bioavailability and sufficient stability to allow oral administration to mammals in need of cancer therapy.
The problem being solved addresses the need for new treatments for cancer, particularly renal cancer, which is a major cause of morbidity and mortality. Prior attempts involved identifying medicinal products from plant materials, such as Phyllanthus species and certain epoxy guaianes, but there remained a desire for new effective cancer treatments.
Claims Coverage
The patent includes two independent claims covering the compound compositions, pharmaceutical compositions, and various therapeutic methods involving these compounds. The inventive features center on chemical structure, pharmaceutical formula, and methods of treatment for cancer and other conditions using these compounds.
Compound of specific aza-epoxy guaiane derivatives
A compound of formula (I) or formula (II), or an epimer thereof, with defined substituents R1 to R6, including aspects where R6 is hydroxy C1-C6 alkyl or fluoro C1-C6 alkyl, and R4 is phenyl, C6-C10 aryl, or C3-C8 cycloalkyl with substitutions.
Pharmaceutical composition comprising the compound
A pharmaceutical composition containing a pharmaceutically acceptable carrier combined with a compound or epimer of the invention as defined in claim 1.
Method of treating various cancers with the compound
A method of treating cancer in a mammal by administering an effective amount of the compound or its epimer as defined in claim 1, where cancer includes leukemia, non-small cell lung cancer, colon cancer, melanoma, prostate cancer, kidney cancer, breast cancer, CNS cancer, Ewing's sarcoma, and ovarian cancer.
Oral administration of the compound for cancer treatment
Administering the compound or epimer orally to the mammal in need, as further defined in the method of cancer treatment claims.
Method of treating diseases associated with insulin resistance
Administering an effective amount of the compound or epimer to treat diseases or conditions associated with insulin resistance such as diabetes, type 2 diabetes, obesity, inflammation, metabolic syndrome, polycystic ovary disease, arteriosclerosis, non-alcoholic fatty liver disease, reproductive abnormality in females, and growth abnormality.
Activation of heat shock protein pathways by the compounds
Methods for activating transcriptional activity of heat shock factor 1 (HSF1) or inducing expression of heat shock protein 70 (HSP70) by administering the compound or epimer.
Treatment methods for HIV and HTLV infections with antiviral co-administration
Treating HIV- or HTLV-infected animals by co-administering the compound or epimer along with at least one antiviral agent, and methods for increasing latent infected CD4+ cell activity, inhibiting Treg activation and number, and decreasing Glut1 expression in infected animals.
Pharmaceutical compositions including the compound and anti-retroviral agents
A pharmaceutical composition containing the compound of formula (I) or (II) along with at least one anti-retroviral agent to treat viral infections as an adjuvant therapy.
The independent claims focus on the specific chemical compounds of formula (I) or (II), their pharmaceutical compositions, and their therapeutic uses for treating cancer, insulin resistance-related diseases, viral infections including HIV and HTLV, and biologically activating heat shock protein pathways. The claims also cover oral administration methods and combination therapies with antiviral agents.
Stated Advantages
The compounds exhibit oral bioavailability and sufficient stability allowing for oral administration to mammals.
They inhibit the growth of multiple cancer cell lines, including renal cancer, breast cancer, CNS cancer, ovarian cancer, colon cancer, leukemia, non-small cell lung cancer, melanoma, and prostate cancer, with GI50 or IC50 values of 1 μM or less, preferably 0.1 μM or less.
Induction of heat shock proteins protects proteins from damage, upregulates antioxidant mechanisms, and may improve conditions associated with insulin resistance and inflammation.
The compounds can be used in combination with existing antiviral agents to improve therapeutic outcomes in HIV and HTLV infections.
Documented Applications
Treatment or prevention of various types of cancer in mammals, including leukemia, non-small cell lung cancer, colon cancer, melanoma, prostate cancer, kidney (renal) cancer, breast cancer, CNS cancer, Ewing's sarcoma, and ovarian cancer.
Treatment of diseases or conditions associated with insulin resistance such as diabetes (including type 2 diabetes), obesity, inflammation, metabolic syndrome, polycystic ovary disease, arteriosclerosis, non-alcoholic fatty liver disease, reproductive abnormalities in females, and growth abnormalities.
Activation of heat shock factor 1 (HSF1) transcriptional activity or induction of heat shock protein 70 (HSP70) expression in animals needing such treatment.
Treatment of HIV and HTLV infections by co-administration of the compounds with antiviral agents, increasing activity of latent infected CD4+ cells, inhibiting regulatory T cell activation and number, and decreasing Glut1 expression in ATL cells in infected animals.
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