ABSTRACT
We disclose here for the first time the curative activity of a new generation of trioxane dimers, designed logically and prepared easily from the natural trioxane artemisinin in only four or five chemical steps that would be easily accomplished also on a manufacturing scale. Four of these trioxane dimers cure malaria-infected mice after only a single subcutaneous dose, and two other dimers cure after three oral doses.
Subject(s)
Antimalarials/chemical synthesis , Artemisinins/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Malaria/drug therapy , Animals , Antimalarials/chemistry , Antimalarials/therapeutic use , Artemisinins/chemistry , Artemisinins/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Malaria/mortality , Mice , Plasmodium berghei , Structure-Activity RelationshipABSTRACT
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
The aim of this study was to synthesise pure enantiomers of potent antimalarial 1,2,4-trioxanes, which are related to the natural antimalarial artemisinin, and then to assay each against a panel of Plasmodium falciparum strains. The working hypothesis was that if the artemisinin derivatives interact with a specific protein-target site, then there should be stereoselective differences in their activity. In five different P. falciparum isolates, however, the trioxane enantiomers (+)-7 a, (-)-7 a and (+)-7 b, (-)-7 b, showed the same level of in vitro antiparasitic activity.
Subject(s)
Antimalarials/pharmacology , Artemisinins/pharmacology , Heterocyclic Compounds/pharmacology , Plasmodium falciparum/drug effects , Animals , Antimalarials/chemical synthesis , Antimalarials/chemistry , Artemisinins/metabolism , Drug Design , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Inhibitory Concentration 50 , Molecular Structure , Parasitic Sensitivity Tests , StereoisomerismABSTRACT
In only four chemical steps from naturally occurring artemisinin (1), trioxane dimers 6 and 7 were prepared on a multigram scale in overall 32-44% yields. In mice, both isonicotinate N-oxide dimer 6 and isobutyric acid dimer 7 were considerably more antimalarially efficacious than clinically used sodium artesunate (2) via both oral and intravenous administration. In the transgenic adenocarcinoma of mouse prostate model, some of the trioxane dimers had potent anticancer activity.
Subject(s)
Antimalarials/chemical synthesis , Antineoplastic Agents/chemical synthesis , Artemisinins/chemical synthesis , Adenocarcinoma , Administration, Oral , Animals , Antimalarials/pharmacology , Antimalarials/toxicity , Antineoplastic Agents/pharmacology , Antineoplastic Agents/toxicity , Artemisinins/pharmacology , Artemisinins/toxicity , Cell Line, Tumor , Dimerization , Drug Resistance , Drug Screening Assays, Antitumor , Flow Cytometry , Injections, Intravenous , Male , Mice , Plasmodium falciparum/drug effects , Prostatic Neoplasms , Structure-Activity RelationshipABSTRACT
In only two steps and in 70% overall yield, naturally occurring trioxane artemisinin (1) was converted on a gram scale into C-10-carba trioxane dimer 3. This new, very stable dimer was then transformed easily in one additional step into four different dimers 4-7. Alcohol and diol dimers 4 and 5 and ketone dimer 7 are 10 times more antimalarially potent in vitro than artemisinin (1), and alcohol and diol dimers 4 and 5 are strongly growth inhibitory but not cytotoxic toward several human cancer cell lines. Water-soluble carboxylic acid derivatives 8aand 9 were easily prepared in one additional step from dimers 4 and 5. Carboxylic acid dimers 8a and 9 are thermally stable even at 60 degrees C for 24 h, are more orally efficacious as antimalarials in rodents than either artelinic acid or sodium artesunate, and are strongly inhibitory but not cytotoxic toward several human cancer cell lines.
Subject(s)
Antimalarials/chemical synthesis , Antineoplastic Agents/chemical synthesis , Artemisinins/chemical synthesis , Administration, Oral , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Artemisinins/chemistry , Artemisinins/pharmacology , Drug Screening Assays, Antitumor , Humans , Malaria/drug therapy , Malaria/parasitology , Mice , Plasmodium berghei , Plasmodium falciparum/drug effects , Polymers , Solubility , Structure-Activity Relationship , Tumor Cells, Cultured , WaterABSTRACT
Mechanism-based rational design and gram-scale chemical synthesis have produced some new trioxane and endoperoxide antimalarial drug candidates that are efficacious and safe. This review summarises recent achievements in this area of peroxide drug development for malaria chemotherapy.
Subject(s)
Antimalarials/pharmacology , Artemisinins/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Peroxides , Plasmodium/drug effects , Sesquiterpenes/pharmacology , Animals , Drug DesignABSTRACT
Chemical insights into artemisinin's biological mechanism of action have allowed rational design of some new trioxane and endoperoxide antimalarial drug candidates that are efficacious and safe. This review summarizes recent achievements in this area of peroxide drug development for malaria chemotherapy.
Subject(s)
Antimanic Agents/therapeutic use , Malaria/drug therapy , Peroxides/therapeutic use , Plasmodium/drug effects , Animals , Antimanic Agents/chemistry , Humans , Molecular Structure , Peroxides/chemistry , Plasmodium/isolation & purification , Structure-Activity RelationshipABSTRACT
Short chemical syntheses of four new antimalarial trioxanes are presented, starting with inexpensive and commercially available cyclohexanone. Almost exclusive formation of the trioxane 12alpha-stereoisomers simplifies product purification. Carboxyphenyltrioxanes 3 and 5 are thermally stable in air even at 60 degrees C for 24 h. When administered orally, these new carboxyphenyltrioxanes are highly efficacious in curing malaria-infected mice. Important for their practical in vivo administration, these new synthetic antimalarial trioxanes 3 and 5 are 14-20 times more soluble in water at pH 7.4 than is artelinic acid (1), a leading semisynthetic, herb-derived antimalarial trioxane drug candidate.
Subject(s)
Antimalarials/chemical synthesis , Benzoates/chemical synthesis , Benzoxepins/chemical synthesis , Administration, Oral , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Benzoates/chemistry , Benzoates/pharmacology , Benzoxepins/chemistry , Benzoxepins/pharmacology , Malaria/drug therapy , Mice , Plasmodium berghei , Solubility , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Joining two 10-deoxoartemisinin trioxane units via a p-diacetylbenzene linker produces new C-10 non-acetal dimers and. 1H NMR spectroscopy allows unambiguous assignment of the stereochemistry at C-10 in these dimers. Successful replacement of both carbonyl oxygen atoms in these diketone dimers by fluorine atoms produces new tetrafluorinated dimers and. Each dimer was evaluated in vitro for antimalarial, antiproliferative, and antitumor activities; ketone dimers and, more than fluorinated dimers and, are promising for chemotherapy of both malaria and cancer.
