Neurotrophic natural products: chemistry and biology

Abstract

Neurodegenerative diseases and spinal cord injury affect approximately 50 million people worldwide, bringing the total healthcare cost to over 600 billion dollars per year. Nervous system growth factors, that is, neurotrophins, are a potential solution to these disorders, since they could promote nerve regeneration. An average of 500 publications per year attests to the significance of neurotrophins in biomedical sciences and underlines their potential for therapeutic applications. Nonetheless, the poor pharmacokinetic profile of neurotrophins severely restricts their clinical use. On the other hand, small molecules that modulate neurotrophic activity offer a promising therapeutic approach against neurological disorders. Nature has provided an impressive array of natural products that have potent neurotrophic activities. This Review highlights the current synthetic strategies toward these compounds and summarizes their ability to induce neuronal growth and rehabilitation. It is anticipated that neurotrophic natural products could be used not only as starting points in drug design but also as tools to study the next frontier in biomedical sciences: the brain activity map project.

Keywords: Alzheimer’s disease; dementia; drug discovery; neurodegenerative disease; total synthesis.

Figure 1

Summary of neurodegenerative diseases (NDDs; AD =Alzheimer’s Disease, ALS =amyotrophic lateral sclerosis, HD =Huntington’s Disease, PD =Parkinson’s Disease) and spinal cord injury (SCI).^[44]

Figure 2

Neurotrophin signaling pathways.

Figure 3

Selected lactacystin analogues.

Figure 4

Structure of fellutamide B (12).

Figure 5

Representative neurotrophic Illicium sesquiterpenes.

Figure 6

Representative structure–activity relationship studies on jiadifenin and analogues. The numbers in parenthesis indicate the extent of neurite outgrowth compared to a control; inactive indicates less than 110% neurite outgrowth as compared to control.

Figure 7

Neurotrophic Lycopodium alkaloids.

Figure 8

Neurotrophic cyathane diterpenoids.

Figure 9

Structure of scabronine M (174).

Figure 10

Neurotrophic trichothecanes.

Figure 11

Neurotrophic manzamine natural products.

Figure 12

Representative neurotrophic steroids.

Figure 13

Representative neurotrophic PPAPs.

Figure 14

Neurotrophic tricholomalides.

Figure 15

Neurotrophic neovibsanes.

Figure 16

Other selected neurotrophic natural products.

Scheme 1

Part of the total synthesis of (+)-lactacystin by Corey et al.^[52] Bn =benzyl, LDA =lithium diisopropylamide, TBS =tert-butyl-dimethylsilyl, TfOH =trifluoromethanesulfonic acid, TMS =trimethyl-silyl.

Scheme 2

Part of the total synthesis of merrilactone A (13) by Danishefsky and co-workers.^[71] AIBN=azobis(isobutyronitrile), TFA = trifluoroacetic acid.

Scheme 3

Part of the total synthesis of merrilactone A (13) by Inoue, Hirama and co-workers.^[75] LiHMDS =lithium hexamethyldisilazide.

Scheme 4

Part of the total synthesis of (±)-merrilactone A (13) by Mehta and Singh.^[76] PCC=pyridinium chlorochromate.

Scheme 5

Part of the total synthesis of (±)-merrilactone A (13) by Frontier and co-workers.^[79] dppe =1,2-bis(diphenylphosphino)ethane, DIB =o-diiodobenzene, TIPS =triisopropylsilyl, TsOH =p-toluenesul-fonic acid.

Scheme 6

Total synthesis of (±)-merrilactone A (13) by Greaney and co-workers.^[82] Cp =cyclopentadienyl, TBAF =tetrabutylammonium fluoride, TES =triethylsilyl.

Scheme 7

Part of the total synthesis of (±)-merrilactone A (13) by Zhai and co-workers.^[84] MVK =methyl vinyl ketone.

Scheme 8

Part of the total synthesis of (±)-jiadifenin (14) by Dani-shefsky and co-workers.^[87]

Scheme 9

Part of the total synthesis of (−)-jiadifenin (14) by Theodorakis and co-workers.^[89]

Scheme 10

Part of the total synthesis of (−)-jiadifenin (14) by Zhai and co-workers.^[91]

Scheme 11

Part of the total synthesis of (−)-jiadifenolide (15) by Theodorakis and co-workers.^[93] mCPBA =m-chloroperbenzoic acid.

Scheme 12

Part of the total synthesis of 11-O-debenzoyltashironin (19) by Danishefsky and co-workers.^[99]

Scheme 13

Part of the total syntheses of tricycloillicinone (21) by Danishefsky et al. and Terashima and Furuya.^[105] TBDPS =tert-butyldi-phenylsilyl.

Scheme 14

Part of the total syntheses of (±)-huperzine A (89) by Xia and Kozikowski as well as Qian and Ji.^[125,126]

Scheme 15

Part of the total synthesis of (−)-huperzine A (89) by Fukuyama and co-workers.^[127]

Scheme 16

Part of the total syntheses of (−)-huperzine A (89) by Herzon and co-workers and Lin and co-workers.^[129,131] Boc =tert-butoxycarbonyl.

Scheme 17

Part of the total synthesis of (+)-lyconadin A (90) and (−)-B (91) by Beshore and Smith.^[136] Cbz =carboxybenzyl, NIS =N-iodosuccinimide.

Scheme 18

Part of the total synthesis of lyconadin A (90) by Sarpong and co-workers.^[137]

Scheme 19

Part of the total syntheses of lyconadins by Fukuyama and co-workers.^[138] Py=pyridine.

Scheme 20

Part of the total synthesis of (+)-complanadine A (94) by Fischer and Sarpong.^[140] [B(pin)]₂ = diboron pinacolato ester, dppf =1,1′-bis(diphenyl phosphino) ferrocene, dtBu-dipy=di-tert-butyl-bipyridine.

Scheme 21

Part of the total synthesis of (+)-complanadine A (94) by Siegel and co-workers.^[144]

Scheme 22

Part of the total syntheses of (+)-nankakurines by Overman and co-workers.^[148]

Scheme 23

Part of the total syntheses of (±)-nankakurines by Cheng and Waters.^[149]

Scheme 24

Part of the total synthesis of (+)-erinacine A (142) by Snider et al.^[159] DMS=dimethylsulfide, HMPA=hexamethylphosphorus amide.

Scheme 25

Part of the total syntheses of (−)-erinacine B (143) and (−)-E (146) by Watanabe and Nakada.^[163] Bz =benzoyl, DBU =1,8-diazabicyclo[5.4.0]undec-7-ene.

Scheme 26

Part of the total synthesis of (−)-scabronine G (152) by Danishefsky and co-workers.^[165]

Scheme 27

Part of the total synthesis of (−)-scabronine G (152) by Kanoh, Iwabuchi et al.^[168] HMDS =hexamethyldisilazane.

Scheme 28

Part of the total synthesis of (+)-cyrneine A (154) by Gademann and co-workers.^[173] TBABr=tetrabutylammonium bromide, TMP =2,2,6,6-tetramethylpiperidine.

Scheme 29

Part of the total synthesis of (±)-paecilomycine A (179) by Min and Danishefsky.^[176] NMO =N-methylmorpholine N-oxide, TPAP =tetrapropylammonium perruthenate.

Scheme 30

Part of the total syntheses of (±)-spirotenuipesine A (180) and B (181) by Danishefsky and co-workers.^[178] PMB =p-methoxyben-zyl.

Scheme 31

Part of the total synthesis of (+)-manzamine A (195) by Winkler and Axten.^[186]

Scheme 32

Part of the total synthesis of (+)-manzamine A (195) by Martin et al.^[187]

Scheme 33

Part of the total synthesis of (+)-manzamine A (195) by Fukuyama and co-workers.^[184] PMP=p-methoxyphenyl.

Scheme 34

Part of the total synthesis of (+)-manzamine A (195) by Dixon and co-workers.^[190]

Scheme 35

Part of the total synthesis of (+)-NGA0187 (217) by Danishefsky and co-workers.^[195]

Scheme 36

Part of the total synthesis of (+)-withanolide A (218) by Gademann and co-workers.^[197] MOM=methoxymethyl, TPP =mesotetraphenylporphyrin.

Scheme 37

Part of the total synthesis of (−)-hyperforin (229) by Kanai, Shibasaki and co-workers.^[216] DMP=Dess–Martin periodinane.

Scheme 38

Part of the total synthesis of (+)-hyperforin (229) by Shair and co-workers.^[218]

Scheme 39

Part of the total synthesis of (±)-garsubellin A (221) by Kanai, Shibasaki and co-workers. ^[220] TBHP =tert-butylhydrogen peroxide.

Scheme 40

Part of the total synthesis of (±)-garsubellin A (230) by Siegel and Danishefsky.^[222] CAN =cerium(IV) ammonium nitrate.

Scheme 41

Part of the total syntheses of (±)-tricholomalides by Danishefsky and co-workers.^[226] TBHP =tert-butylhydrogen peroxide.

Scheme 42

Part of the total synthesis of (±)-neovibsanin B (263) by Imagawa, Nishizawa et al.^[229b] DMPM=3,4-dimethoxybenzyl.

Scheme 43

Part of the total synthesis of (+)-neovibsanin B (254) by Esumi, Fukuyama et al.^[229c]