23-hydroxybetulinic-acid and Neoplasms

The vast research and clinical result have verified the success of cancer immunotherapy. However, there is also facing the enormous challenges such as lack of precise pre-clinical models, optimal combined therapy regimen and acquired resistance to immunotherapy. Adenosine is a potent immune-modulating molecule and overexpression of CD73 on tumor leads to the high concentration of adenosine. Blockade of the key adenosine-generating enzyme CD73 can be a promising strategy for cancer immunotherapy. Here, we report the discovery of betulinic acid as a novel CD73 inhibitor lead compound by a hit-based substructure search strategy. Subsequent optimization led to the discovery of betulinic acid carbamate derivative ZM514 with 5.2-fold increased potency compared to lead compound. Simultaneously, study has showed that compound ZM514 was not a cytotoxic agent while betulinic acid showed modest antiproliferative activity. The present result provides a valuable inhibitor against the promising immuno-oncology target for further development.

Topics: 5'-Nucleotidase; Adenosine; Betulinic Acid; Humans; Immunotherapy; Neoplasms; Pentacyclic Triterpenes

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.

Topics: Animals; Antineoplastic Agents; Drug Screening Assays, Antitumor; HeLa Cells; HL-60 Cells; Humans; Mice; Neoplasms; Triterpenes

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.

Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Proliferation; Humans; Liver Neoplasms; Melanoma, Experimental; Mice; Molecular Structure; Neoplasms; Structure-Activity Relationship; Triterpenes; Tumor Cells, Cultured; Xenograft Model Antitumor Assays