ABSTRACT
Pyrazine-fused 23-hydroxybetulinic acid was synthesized by introducing a pyrazine ring between C-2 and C-3 position and further modifications were carried out by substitution of C-28 carboxyl group by ester and amide linkage to enhance the antitumor activity. The biological screening results showed that all of the derivatives exhibited more significant antiproliferative activity than the parent compound. In particular compound 12a exhibited the most potent activity with IC50 values of 3.53 µM, 4.42 µM and 5.13 µM against cell lines SF-763, B16 and Hela, respectively. In the preliminary mechanism study, 12a caused cell arrest in G1 phase and significantly induced apoptosis of B16 cells in a dose-dependent manner. Furthermore, the in vivo antitumor activity of 12a was validated (tumor inhibitory ratio of 55.6% and 62.7%, respectively) in mice with H22 liver cancer and B16 melanoma.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Drug Design , Liver Neoplasms/drug therapy , Melanoma, Experimental/drug therapy , Morpholines/chemical synthesis , Morpholines/pharmacology , Pyrazines/chemistry , Triterpenes/chemistry , Animals , Apoptosis/drug effects , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , G1 Phase/drug effects , HeLa Cells , Humans , Liver Neoplasms/pathology , Melanoma, Experimental/pathology , Mice , Molecular Structure , Pyrazines/chemical synthesis , Pyrazines/pharmacology , Structure-Activity RelationshipABSTRACT
A collection of isoxazole and oxadiazole substituted 23-hydroxybetulinic acid (HBA) derivatives were designed, synthesized and evaluated for their antitumor activity. Most of the newly synthesized compounds exhibited more potent antiproliferative activity than patent compound 23-hydroxybetulinic acid, especially 13e and 14a were about four- to sevenfold more potent against all tested cancer cell lines than 23-hydroxybetulinic acid. Furthermore, the in vivo antitumor activity of 13e and 14a was validated in H22 liver cancer and B16 melanoma xenograft mouse models. The structure-activity relationships of these 23-hydroxybetulinic acid derivatives were also discussed based on the present investigation.
Subject(s)
Antineoplastic Agents , Neoplasms/diet therapy , Triterpenes , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Screening Assays, Antitumor , HL-60 Cells , HeLa Cells , Humans , Mice , Triterpenes/chemistry , Triterpenes/pharmacologyABSTRACT
Ambradiolic acid (3) with oleanane skeleton is a natural pentacyclictriterpene. The first synthesis of 3 starting from 23-hydroxybetulinic acid (2) has been accomplished in 12-steps with a total yield of 18.1% in our study. Compound 3 was further biologically evaluated and found to exhibit significant inhibitory activity against rabbit muscle glycogen phosphorylase (GP) with an IC50 value of 12.4 µM, suggesting it could be a potential lead compound for the development of hypoglycemic drugs.
Subject(s)
Enzyme Inhibitors/pharmacology , Glycogen Phosphorylase/antagonists & inhibitors , Oleanolic Acid/analogs & derivatives , Pentacyclic Triterpenes/pharmacology , Animals , Enzyme Inhibitors/chemical synthesis , Molecular Structure , Muscle, Skeletal/enzymology , Oleanolic Acid/chemical synthesis , Oleanolic Acid/chemistry , Oleanolic Acid/pharmacology , Pentacyclic Triterpenes/chemical synthesis , Rabbits , Structure-Activity Relationship , Triterpenes/chemistryABSTRACT
A collection of pyrazole-fused 23-hydroxybetulinic acid derivatives were designed, synthesized and evaluated for their antitumor activity. Most of the newly synthesized compounds exhibited significant antiproliferative activity. Especially compound 15e displayed the most potent activity with the IC50 values of 5.58 and 6.13µM against B16 and SF763 cancer cell lines, respectively. Furthermore, the significant in vivo antitumor activity of 15e was validated in H22 liver cancer and B16 melanoma xenograft mouse models. The structure-activity relationships of these 23-hydroxybetulinic acid derivatives were also discussed based on the present investigation.
Subject(s)
Antineoplastic Agents/chemical synthesis , Pyrazoles/chemistry , Triterpenes/chemistry , Animals , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/toxicity , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Disease Models, Animal , Drug Screening Assays, Antitumor , Humans , Liver Neoplasms/drug therapy , Melanoma, Experimental/drug therapy , Mice , Structure-Activity Relationship , Transplantation, Heterologous , Triterpenes/therapeutic use , Triterpenes/toxicityABSTRACT
A series of novel derivatives of 3-oxo-23-hydroxybetulinic acid was designed, synthesized, and evaluated for their antiproliferative activity against a panel of cancer cell lines (HL-60, BEL-7402, SF-763, HeLa, B16 and A375). The results indicated that majority of the derivatives exhibited more significant antitumor activity than the parent compound. In particular compound 10e showed the most potent activity with IC50 values of 5.85, 6.23 and 7.22 µM against B16, SF-763 and BEL-7402 cells, respectively. Furthermore, 10e inhibited tumor growth by 51.8% and 62.7% (w/w) in H22 and B16 xenograft mouse models, comparable to cyclophosphamide and 5-fluorouracil, respectively.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Melanoma, Experimental/drug therapy , Neoplasms/drug therapy , Triterpenes/chemistry , Animals , Carcinoma, Hepatocellular/pathology , Cell Proliferation/drug effects , Humans , Liver Neoplasms/pathology , Melanoma, Experimental/pathology , Mice , Molecular Structure , Neoplasms/pathology , Structure-Activity Relationship , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
A series of 23-hydroxybetulinic acid derivatives were prepared and tested in vitro as a new class of inhibitors of glycogen phosphorylase (GP). Within this series of compounds, 12b (IC(50)=3.5 microM) is the most potent GPa inhibitor. The preliminary SAR results of the 23-hydroxybetulinic acid derivatives are discussed.