Indole-Containing Natural Products 2019-2022: Isolations, Reappraisals, Syntheses, and Biological Activities

Abstract

Indole alkaloids represent a large subset of natural products, with more than 4100 known compounds. The majority of these alkaloids are biologically active, with some exhibiting excellent antitumor, antibacterial, antiviral, antifungal, and antiplasmodial activities. Consequently, the natural products of this class have attracted considerable attention as potential leads for novel therapeutics and are routinely isolated, characterized, and profiled to gauge their biological potential. However, data on indole alkaloids, their various structures, and bioactivities are complex due to their diverse sources, such as plants, fungi, bacteria, sponges, tunicates, and bryozoans; thus, isolation methods produce an incredible trove of information. The situation is exacerbated when synthetic derivatives, as well as their structures, bioactivities, and synthetic schemes, are considered. Thus, to make such data comprehensive and inform researchers about the current field's state, this review summarizes recent reports on novel indole alkaloids. It deals with the isolation and characterization of 250 novel indole alkaloids, a reappraisal of previously reported compounds, and total syntheses of indole alkaloids. In addition, several syntheses and semi-syntheses of indole-containing derivatives and their bioactivities are reported between January 2019 and July 2022.

Keywords: anticancer; antimicrobial; antiviral; cytotoxic; indole; natural products; other bioactivities.

Figure 1

Distribution of the sources of novel indole alkaloids.

Figure 2

Distribution of indole alkaloids across plant, tree, and fungal sources.

Figure 3

Novel indole alkaloids 1 to 18.

Figure 4

Novel indole alkaloids 19 to 50.

Figure 5

Novel indole alkaloids 51 to 70.

Figure 6

Novel indole alkaloids 71 to 98.

Figure 7

Novel indole alkaloids 99 to 126.

Figure 8

Novel indole alkaloids 127 to 154.

Figure 9

Novel indole alkaloids 155 to 195.

Figure 10

Novel indole alkaloids 196 to 216.

Figure 11

Novel indole alkaloids 217 to 250.

Figure 12

Reappraised structures of cottoquinazolines (E–G) 251–253.

Figure 13

Reappraised structures of echinosulfone A and echinosulfonic acids (A–D) 254–258.

Figure 14

Reappraised structure of protoaculeine B 259.

Figure 15

Revised structure of lyaline 260.

Figure 16

The total synthesis of (±)-conolidine 269. (a) n-BuLi, THF, −78 °C, 5 min, then rt, 1 h, then N-tosylpyrrolidonein THF, −30 °C to −15 °C, 4 h, 48%; (b) K₂CO₃, 1-bromo-2-butyne, CH₃CN, 80 °C, 94%; (c) TBAF, CH₃CN 35 °C, 15 h, 93%; (d) TiPSOTf, 2,6-lutidine, 35 °C, 5 h, 97%, E:Z = 8:92; (e) [JohnPhosAu(CH₃CN)]SbF6, H₂O, toluene, 60 °C, 2 h, 15% for 266, 73% for 267; (f) Sodium naphthalenide, THF, −78 °C, 86%; (g) (CH₂O)n, TFA, CH₃CN, reflux, 2 h, 82%.

Figure 17

The total synthesis of psammocindoles (A–D) 212–214, 286, and their isomers 287–290. (a) Ethyl bromoacetate, DCM, Et₃N, rt, 2 h, 90–93%; (b) Propionyl chloride, Et₃N, 0 °C to rt, 1.5 h, 94–95%; (c) NaH, THF, reflux, 12 h, 83–86%; (d) Indole, BF₃-Et₂O, 4 Å MS, PhCl, 100 °C, 1.5 h, 27–31%.

Figure 18

The total synthesis of amakusamine 233. (a) NBS, conc. H₂SO₄, 63%; (b) (1) Al₂O₃, CH₃NO₂ and (2) Ac₂O; (c) Iron in AcOH, (last two steps) 89%.

Figure 19

Amakusamine derivatives synthesized 294–308.

Figure 20

The total synthesis of griseofamine B (314) and its isomers 317, 321, and 323. (a) Boc₂O, Et₃N, DMAP, DCM, reflux, 2 h, 90%; (b) 2-methyl-3-buten-2-ol, PdCl₂(PPh₃)₄, Ag₂CO₃, Et₃N, 1,4-dioxane, 100 °C, 6 h; 67% (c) PdCl₂(CH₃CN)₂, CH₃CN, reflux, 2 h; E:Z = 56–58%:15–16% (d) TMSOTf, 2,6-lutidine, DCM, rt, overnight, 87–88%; (e) diketene, Et₃N, DCM, rt, overnight, 62–63%.

Figure 21

Synthesis of hydroxamic derivatives 347–352. (a) SOCl₂, CH₃OH, 0 °C, 1 h, and then 65 °C, 4 h; (b) ω-Dibromoalkane, K₂CO₃, CH₃CN, reflux, 4 h, 66–75%; (c) 4-methoxybenzaldehyde, AcOH, reflux, 4 h; (d) Thionyl chloride, CH₃OH, 0 °C, 1 h, and then 65 °C, 6 h; (e) KMnO₄, DMF, rt, 5 h; (f) Hydrazine monohydrate, CH₃OH, 50 °C, 6 h; (g) NaNO₂, HCl; (h) AcOH, H₂O, 50 °C, 6 h; (i) 328–333, K₂CO₃, CH₃CN, reflux, 12 h; (j) NH₂OK, CH₃OH, rt, 8–12 h, 46–56%.

Figure 22

Synthesis of neopeltolide derivatives 404 to 424 and 438 to 443. (a) NaHCO₃, 1,4-dioxane, rt, 95%; (b) n-BuLi, CO₂, THF, −78 °C, 84%; (c) H₂, Lindlar’s catalyst, EtOAc, 91%; (d) l-Serine methyl ester hydrochloride, i-BuOCOCl, N-CH₃-morpholine, THF, 75%; (e) (1) DAST, DCM, −78 °C and (2) BrCCl3, DBU, −20 °C, 62%; (f) LiOH, THF/H₂O, 88%; (g) NCS, HCl, THF, 82%; (h) Substituted benzyl chlorides, NaH, DMF, rt, quantitative; (i) DIBAL-H, THF, −78 °C, 57–75%; (j) 359, EDCI, HOBt, Et₃N, DMF, 43–71%; (k) substituted benzyl bromides, NaH, DMF, rt, quantitative; (l) Fe, NH4Cl, H₂O, EtOH, reflux, 53–67%; (m) 359, EDCI, HOBt, DMF, 49–70%.

Figure 23

Synthesis of celastrol derivatives 456 to 465. (a) NaHCO₃, propargyl bromide, DMF, rt, 78%; (b) substituted indoles, FeCl₃.6H₂O, DCM; (c) Ac₂O, DMAP, DCM, 37–54%.

Figure 24

Synthesis of phidianidine A derivatives 479 to 488. (a) Boc₂O, rt, overnight, 93–95%; (b) (1) Boc₂O, Et₃N, rt, 2 h, (2) MsCl, Et₃N, 0 °C, 5 h and (3) CH₃NH₂, 60 °C, 1 h, 58%; (c) oxalyl chloride, 30 min, 77%; (d) (1) Hydrazine, 80 °C, MW, 15 min and (2) NaOCH₃, 80 °C, MW, 15 min, 80%; (e) (1) 470–473, 475, DIPEA, HATU, 1.5 h and (2) TFA, DCM, 4 h, 8–73%; (f) (1) 479–481, 483, 489, DIPEA, 3 h and (2) TFA, DCM, 2 h, 24–83%; (g) 479, CH₂O, NaBH₃CN, AcOH, 21 h and (2) CH₃I, 0 °C, 53%.

Figure 25

Synthesis of fradcarbazole A derivatives 535 to 548. (a) Boc₂O, Et₃N, THF, 10 °C, 83–99%; (b) DDQ, THF/H₂O 0 °C, 58–81%; (c) TFA, 10 °C, 72–94%; (d) Boc₂O, Et₃N, THF, 0 °C, 76%; (e) NBS, CH₃OH, DCM, 0 °C, 94%, or NCS, CH₃OH, DCM, rt, 48%; (f) TFA, DCM, 0 °C, 50–93%; (g) TCDI, Et₃N, DCM, rt, 71–88%; (h) TCDI, Et₃N, DCM, rt, 82%; (i) CH₃I, CH₃CN, rt, 68–74%; (j) 504–508, Et₃N, DMF, rt, 38–56%; (k) (CF₃CO)₂O, DCM, EtOH, 0 °C, 47–81%.

Figure 26

The semi-synthesis of (−)-melodinine K 556. (a) T16H yeast, 64%; (b) Allyl bromide, K₂CO₃, DMF, 68%; (c) NaH, TrocCl, THF/DMF 0 °C, 92%; (d) TFA then m-CPBA, DCM, −10 °C then rt, 38%; (e) m-CPBA, DCM, 0 °C, 36%; (f) (1) TFAA, DCM, 0 °C to rt and (2) 551, DCM, 78%; (g) (1) Pd(PPh₃)₄, pyrrolidine, DCM, rt and (2) Zn, KH₂PO₄, THF, 60 °C, 40%.

Figure 27

The semi-synthesis of 5-methylpsilocybin 561. (a) Ac₂O, NaHCO₃, toluene, 97%; (b) (1) oxalyl chloride and (2) (CH₃)₂NH, THF, 77%; (c) LiAlH₄, THF, 84%; (d) PsiK, ATP, MgCl₂, H₂O, 16 h, 44%.