ABSTRACT
The mechanisms of action of three C-10 non-acetal trioxane dimers (TDs) were examined in human (LNCaP) and mouse (TRAMP-C1A and -C2H) prostate cancer cell lines. 1 (AJM3/23), 2 (GHP-TM-III-07w), and 3 (GHP-KB-06) inhibited cell growth with 3 being the most potent in C1A (GI50 = 18.0 nM), C2H (GI50 = 17.0 nM), and LNCaP (GI50 = 17.9 nM) cells. In comparison to a standard cytotoxic agent such as doxorubicin (GI50 = 45.3 nM), 3 (GI50 = 17.9 nM) inhibited LNCaP cell growth more potently. TDs induced G0/G1 cell cycle arrest in LNCaP cells and decreased cells in the S phase. These changes correlated with modulation of G1 phase cell cycle proteins including decreased cyclin D1, cyclin E, and cdk2 and increased p21waf1 and p27Kip1. TDs also promoted apoptosis in LNCaP cells with increased expression of proapoptotic bax. These results demonstrate that TDs are potentially useful agents that warrant further preclinical development for treatment of prostate cancer.
Subject(s)
Acetals/pharmacology , Antineoplastic Agents/pharmacology , Artemisinins/pharmacology , Heterocyclic Compounds/pharmacology , Prostatic Neoplasms/pathology , Acetals/chemical synthesis , Acetals/chemistry , Animals , Antibiotics, Antineoplastic/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Artemisinins/chemical synthesis , Artemisinins/chemistry , Cell Cycle/drug effects , Cell Cycle Proteins/metabolism , Dimerization , Doxorubicin/pharmacology , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Humans , Male , Mice , Prostatic Neoplasms/metabolism , Tumor Cells, Cultured/drug effectsABSTRACT
In only two steps and in 63% overall yield, naturally occurring 1,2,4-trioxane artemisinin (1) was converted into C-10-carba trioxane conjugated diene dimer 4. This new dimer was then transformed easily in one additional 4 + 2-cycloaddition step into phthalate dimer 5, and further modification led to bis-benzyl alcohol dimer 7 and its phosphorylated analogues 8 and 9. Bis-benzyl alcohol dimer 7 is the most antimalarially active in vitro, 10 times more potent than artemisinin (1). Bis-benzyl alcohol dimer 7 is approximately 1.5 times more orally efficacious in rodents than the antimalarial drug sodium artesunate and is about 37 times more efficacious than sodium artesunate via subcutaneous administration. Both dimers 5 and 7 are thermally stable neat even at 60 degrees C for 24 h. Phthalate dimer 5 is very highly growth inhibitory but not cytotoxic toward several human cancer cell lines; both dimers 5 and 7 very efficiently and selectively kill human cervical cancer cells in vitro in a dose-dependent manner with no cytotoxic effects on normal cervical cells.
Subject(s)
Antimalarials/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Artemisinins/chemistry , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Plasmodium falciparum/drug effects , Sesquiterpenes/chemistry , Administration, Oral , Animals , Antimalarials/administration & dosage , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Dimerization , Heterocyclic Compounds/administration & dosage , Heterocyclic Compounds/chemical synthesis , Humans , Molecular StructureABSTRACT
The new 24-phenylsulfone 4a, a low-calcemic analog of the natural hormone 1alpha,25-dihydroxyvitamin D(3), is a potent (IC(50) = 28nM) and highly selective inhibitor of the human 24-hydroxylase enzyme CYP24.
