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Review
. 2022 Oct 24;27(21):7187.
doi: 10.3390/molecules27217187.

Sources, Transformations, Syntheses, and Bioactivities of Monoterpene Pyridine Alkaloids and Cyclopenta[c]pyridine Derivatives

Xuejian Zhang  1   2 , Feiyan Tao  1   2   3 , Tao Cui  1 , Cheng Luo  1 , Zhigang Zhou  1 , Yuchuan Huang  1   2 , Lanlan Tan  1   3 , Wei Peng  4 , Chunjie Wu  4
Affiliations
Review

Sources, Transformations, Syntheses, and Bioactivities of Monoterpene Pyridine Alkaloids and Cyclopenta[c]pyridine Derivatives

Xuejian Zhang et al. Molecules. .

Abstract

Monoterpene pyridine alkaloids (MTPAs) are alkaloids derived from iridoid glycosides (IGs). The common molecular structure of MTPAs is the pyridine ring, while some of them have a cyclopenta[c]pyridine skeleton. Some compounds containing this structure are potentially bioactive medicinal agents. In this paper, seven drug candidates (A-G), ninety natural source products (1-90), thirty-seven synthesized compounds (91-127), as well as twenty-six key intermediates (S1-S26) were summarized. We categorized five types of MTPAs and one type of cyclopenta[c]pyridine alkaloids in all. Additionally, their possible genetic pathways were proposed. Then, the chemical transformation, biotransformation, chemical synthesis, as well as the bioactivity of MTPAs and cyclopenta[c]pyridine derivatives were analyzed and summarized. Cyclopenta[c]pyridine derivatives can be concisely and chirally synthesized, and they have shown potentials with antibacterial, insecticidal, antiviral, anti-inflammatory, and neuropharmacological activities.

Keywords: bioactivity; cyclopenta[c]pyridine derivatives; monoterpene pyridine alkaloids; source; synthesis; transformation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 2
Figure 2
Structures of pyridine alkaloids derived from 4-demethyliridoids (Type I).
Figure 3
Figure 3
Structures of pyridine alkaloids derived from iridoids (Type II).
Figure 4
Figure 4
Pyridine alkaloids derived from hemiacetal secoiridoid (Type III).
Figure 5
Figure 5
Structures of pyridine alkaloids derived from secoiridoids (Type IV).
Figure 6
Figure 6
Structures of pyridines alkaloids derived from lactone secoiridoids (Type V).
Figure 7
Figure 7
Structures of phenyl-substituted cyclopenta[c]pyridine derivatives (Type VI).
Figure 1
Figure 1
Examples of bioactive cyclopenta[c]pyridine derivatives.
Scheme 1
Scheme 1
Possible genetic pathways from iridoids to MTPAs.
Scheme 2
Scheme 2
Possible ammonization and aromatization pathway from iridoids to MTPAs.
Scheme 3
Scheme 3
Proposed genetic pathway for (±)-27 and (±)-28.
Scheme 4
Scheme 4
Amination of secoiridoid glycosides ((A), oleuropein and ligstroside as substrates; (B), methyloleoside as substrates) to give monomeric pyridine, dimeric pyridine, and naphthyridine alkaloids.
Scheme 5
Scheme 5
MTPAs produced from IGs.
Scheme 6
Scheme 6
Possible transformation mode to afford a monomeric MTPA (88) and the dimeric MTPA (40).
Scheme 7
Scheme 7
Possible biosynthetic route of compound 89.
Scheme 8
Scheme 8
Compound 57 yielded from Aspergillus niger (A) or Cordyceps sinensis (B) by means of biotransformation.
Scheme 9
Scheme 9
Conversion of three harpagide congeners to aucubinine B (5) by β-glucosidase in the presence of NH4OAc or by human intestinal flora (A); possible metabolic processes of aucubin by human intestinal bacteria (B).
Scheme 10
Scheme 10
One-step synthesis of the monoterpene natural product, (−)-actinidine (29).
Figure 8
Figure 8
Cyclopenta[c]pyridine products (91–112) obtained from a concise biomimic access.
Scheme 11
Scheme 11
(A), Synthesis of cyclopenta[c]pyridine from genipin; (B), possible reaction mechanism.
Scheme 12
Scheme 12
Reactions afforded cyclopenta[c]pyridine derivatives.
Scheme 13
Scheme 13
The Kondrat’eva Reaction in Flow: synthesis of annulated pyridines.
Scheme 14
Scheme 14
Diastereoselective synthesis of actinidine (4).
Scheme 15
Scheme 15
Total synthesis of the monoterpene alkaloids (−)-plectrodorine (127) and (+)-oxerine (20).
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