An Overview of Biotransformation and Toxicity of Diterpenes

Abstract

Diterpenes have been identified as active compounds in several medicinal plants showing remarkable biological activities, and some isolated diterpenes are produced at commercial scale to be used as medicines, food additives, in the synthesis of fragrances, or in agriculture. There is great interest in developing methods to obtain derivatives of these compounds, and biotransformation processes are interesting tools for the structural modification of natural products with complex chemical structures. Biotransformation processes also have a crucial role in drug development and/or optimization. The understanding of the metabolic pathways for both phase I and II biotransformation of new drug candidates is mandatory for toxicity and efficacy evaluation and part of preclinical studies. This review presents an overview of biotransformation processes of diterpenes carried out by microorganisms, plant cell cultures, animal and human liver microsomes, and rats, chickens, and swine in vivo and highlights the main enzymatic reactions involved in these processes and the role of diterpenes that may be effectively exploited by other fields.

Keywords: biotransformation; diterpenes; toxicity.

Figure 1

Conformational folds of geranylgeranyl diphosphate (GGPP) to copalyl diphosphate stereoisomers [10].

Figure 2

Common diterpene skeletal types.

Figure 3

Proposed metabolites of yuanhuapine (1) detected in rat urine after oral administration [49].

Figure 4

Proposed chemical structures of oridonin (2) metabolites in rats in vivo [50].

Figure 5

Proposed biotransformation metabolites of tiamulin (3) obtained in animals in vivo and in rats, swine, chickens, cows and goat liver microsomes [38].

Figure 6

Proposed phase I and phase II metabolites from rat bile biotransformation of tanshinone I (4) and dihydrotanshinone I (5) [45].

Figure 7

Proposed metabolic pathways and enzyme isoforms involved in the biotransformation of tanshinone I (4) by human liver microsomes and S9 subcellular fractions [52].

Figure 8

Bioconversion of tanshinone IIA (6) in tanshisorbicin (6.2) by Hypocrea sp. [53].

Figure 9

Derivatives 7.1–7.7 of cryptotanshinone (7) obtained by biotransformation with Mucor rouxii [54].

Figure 10

Derivatives (8.1–8.5) of pseudolaric acid (8) obtained by Chaetomium globosum biotransformation [46].

Figure 11

Diterpenoids 9 and 10 and their derivatives obtained by Fusarium oxysporum and Myrothecium verrucaria biotransformation [55].

Figure 12

Andrographolide (11) and its derivatives 11.1–11.10 obtained by Rhizopus stolonifer biotransformation [57].

Figure 13

Biotransformation of agallochaexcoerin A (12) in agallochaexcoerin G (12.1) by Aspergillus flavus [58].

Figure 14

Biotransformation of compound 13 by Streptomyces griseus and its derivatives 13.1, 13.2, and 13.3 [59].

Figure 15

Epoxidation (14.1) and halogenation (14.2) of sclareol (14) by Botrytis cinerea [60].

Figure 16

Chemical structures of 15 and its derivatives 15.1, 15.2 and 15.3 obtained by biotransformation with Rhizopus stolonifer [64].

Figure 17

Chemical structures of the derivatives 16.1, 16.2, and 16.3 obtained by biotransformation of trachyloban-19-oic acid (16) with Syncephalastrum racemosum [65].

Figure 18

Chemical structures of ingenol-3-angelate (17) and its derivatives 17.1, 17.2, and 17.3 obtained by biotransformation with plant cell cultures [66].

Figure 19

Structures of cyanthwigin B (18) and its derivatives 18.1–18.6 obtained by biotransformation with actinomycete Streptomyces sp. [67].

Figure 20

Chemical structures of diterpenes 19–28 [100,101].

Figure 21

Chemical structures of diterpenes 29–36 [98,102].

Figure 22

Chemical structures of diterpenes 37–49 [103].

Figure 23

Chemical structures of diterpenes 50–55 [105].

Figure 24

Chemical structures of diterpenes 56 and 57 [108].

Figure 25

Chemical structures of diterpenes 58 and 59 [109,110].

Figure 26

Chemical structures of diterpenes 60–64 [111].

Figure 27

Chemical structures of diterpenes 65 and 66 [112].