Pentacyclic triterpenes are important representatives of natural products that exhibit a wide variety of biological activities. These activities suggest that these compounds may represent potential medicines for the treatment of cancer and viral, bacterial, or protozoal infections. Naturally occurring triterpenes usually have several drawbacks, such as limited activity and insufficient solubility and bioavailability; therefore, they need to be modified to obtain compounds suitable for drug development. Modifications can be achieved either by methods of standard organic synthesis or with the use of biocatalysts, such as enzymes or enzyme systems within living organisms. In most cases, these modifications result in the preparation of esters, amides, saponins, or sugar conjugates. Notably, while standard organic synthesis has been heavily used and developed, the use of the latter methodology has been rather limited, but it appears that biocatalysis has recently sparked considerably wider interest within the scientific community. Among triterpenes, derivatives of lupane play important roles. This review therefore summarizes the natural occurrence and sources of lupane triterpenoids, their biosynthesis, and semisynthetic methods that may be used for the production of betulinic acid from abundant and inexpensive betulin. Most importantly, this article compares chemical transformations of lupane triterpenoids with analogous reactions performed by biocatalysts and highlights a large space for the future development of biocatalysis in this field. The results of this study may serve as a summary of the current state of research and demonstrate the potential of the method in future applications.

• Keywords
• betulin, betulinic acid, biocatalysis, biotransformation, enzyme, extraction, lupane, lupeol, prodrugs, synthesis,
• MeSH
• Biocatalysis * MeSH
• Hydrolysis MeSH
• Drug Discovery MeSH
• Oxidation-Reduction MeSH
• Triterpenes chemical synthesis   chemistry   MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• lupane MeSH Browser
• Triterpenes MeSH

In this work, we describe synthesis of conjugates of betulinic acid with substituted triazoles prepared via Huisgen 1,3-cycloaddition. All compounds contain free 28-COOH group. Allylic bromination of protected betulinic acid by NBS gave corresponding 30-bromoderivatives, their substitution with sodium azides produced 30-azidoderivatives and these azides were subjected to CuI catalysed Huisgen 1,3-cycloaddition to give the final conjugates. Reactions had moderate to high yields. All new compounds were tested for their in vitro cytotoxic activities on eight cancer and two non-cancer cell lines. The most active compounds were conjugates of 3β-O-acetylbetulinic acid and among them, conjugate with triazole substituted by benzaldehyde 9b was the best with IC50 of 3.3 μM and therapeutic index of 9.1. Five compounds in this study had IC50 below 10 μM and inhibited DNA and RNA synthesis and caused block in G0/G1 cell cycle phase which is highly similar to actinomycin D. It is unusual that here prepared 3β-O-acetates were more active than compounds with the free 3-OH group and this suggests that this set may have common mechanism of action that is different from the mechanism of action of previously known 3β-O-acetoxybetulinic acid derivatives. Benzaldehyde type conjugate 9b is the best candidate for further drug development.

• MeSH
• Benzaldehydes chemistry   MeSH
• Cell Cycle drug effects   MeSH
• Cycloaddition Reaction MeSH
• Betulinic Acid MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Pentacyclic Triterpenes MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Triazoles chemistry   MeSH
• Triterpenes chemistry   MeSH
• Cell Survival drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• benzaldehyde MeSH Browser
• Benzaldehydes MeSH
• Betulinic Acid MeSH
• Pentacyclic Triterpenes MeSH
• Antineoplastic Agents MeSH
• Triazoles MeSH
• Triterpenes MeSH