Monoterpenoid Indole Alkaloids, CNS and Anticancer Drugs

Nemes, András

doi:10.1002/9783527630035.ch8

Cited by 6 publications

(4 citation statements)

References 95 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Natural products and their derivatives have historically served as important sources of building blocks and lead molecules for drug discovery campaigns. , The eburnamine-vincamine alkaloids, found in the Vinca minor plant, are known to exert interesting pharmacological effects, especially cerebral ones. − The parent monoterpenoid indole alkaloid, vincamine (VINC, Figure ), is used as a peripheral vasodilator to enhance cerebral blood flow . Several synthetic derivatives (Figure ) of the eburnamine-vincamine group have demonstrated neuropharmacological effects in preclinical models, but their clinical development has been discontinued probably due to the insufficient achievement of efficacy end points. − However, this alkaloid group has great potential for neuropharmacotherapy and could serve as a core for the development of new compounds.…”

Section: Introductionmentioning

confidence: 99%

Antidepressant-like Effect of the Eburnamine-Type Molecule Vindeburnol in Rat and Mouse Models of Ultrasound-Induced Depression

Zubkov,

Riabova,

Zorkina

et al. 2024

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Vindeburnol (VIND, RU24722, BC19), a synthetic molecule derived from the eburnamine-vincamine alkaloid group, has many neuropsychopharmacological effects, but its antidepressant-like effects are poorly understood and have only been described in a few patents. To reliably estimate this effect, vindeburnol was studied in a model of long-term variable-frequency ultrasound (US) exposure at 20–45 kHz in male Wistar rats and BALB/c mice. Vindeburnol was administered chronically for 21 days against a background of simultaneous ultrasound exposure at a dose of 20 mg/kg intraperitoneally (IP). Using four behavioral tests, the sucrose preference test (SPT), the social interaction test (SIT), the open field test (OFT), and the forced swimming test (FST), we found that the treatment with the compound diminished depression-like symptoms in mice and rats. The compound restored the ultrasound-related reduced sucrose consumption to control levels and increased social interaction time in mice and rats compared with those in ultrasound-exposed animals. Vindeburnol showed contraversive results of horizontal and vertical activity in both species and generally did not increase locomotor activity. At the same time, the compound showed a specific effect in the FST, significantly reducing the immobility time. Moreover, we found an increase in norepinephrine, dopamine, and its metabolite levels in the brainstem, as well as an increase in dopamine, 3-methoxytyramine, and 3,4-dihydroxyphenylacetic acid levels in the striatum. We also observed a statistically significant increase in tyrosine hydroxylase (TH) levels in the region containing the locus coeruleus (LC). We suggest that using its distinct chemical structure and pharmacological activity as a starting point could boost antidepressant drug discovery.

show abstract

Section: Introductionmentioning

confidence: 99%

Antidepressant-like Effect of the Eburnamine-Type Molecule Vindeburnol in Rat and Mouse Models of Ultrasound-Induced Depression

Zubkov,

Riabova,

Zorkina

et al. 2024

ACS Chem. Neurosci.

View full text Add to dashboard Cite

show abstract

“… The core structures of these alkaloids share a unique pentacyclic skeleton containing an indolo[2,3- a ]quinolizine moiety and two consecutive stereogenic centers at the C20/C21 positions, thus resulting in a cis -fused D/E ring system. Such a structural/stereochemical feature coupled with an array of outstanding pharmacological properties has prompted substantial investigations on the chemical syntheses of these alkaloids, which have been widely exploited for both natural and semisynthetic drug discovery and development efforts …”

mentioning

confidence: 99%

Stereoselective Total Syntheses of C18-Oxo Eburnamine-Vincamine Alkaloids

et al. 2022

View full text Add to dashboard Cite

Here, we disclose the divergent total syntheses of representative C18-oxo eburnamine-vincamine alkaloids (+)-eburnaminol, (−)-larutenine, and (−)-cuanzine. Key to the approach is a substrate-controlled iridium-catalyzed asymmetric hydrogenation/lactamization cascade that leads to the formation of the common tetracyclic skeleton with essential cis-C20/C21 stereochemistry (93% yield, 98% ee, >20:1 dr, gram scale). Access to the targeted alkaloids is effected late in the synthesis by implementation of a number of diversity-oriented transformations and late-stage modifications.

show abstract

“…Monoterpenoid indole alkaloids (MIAs) comprise an important group of natural secondary metabolites (including camptothecin (CPT), ajmaline, vindoline, quinine, and others; Figure ), and they are famous for their diverse structural skeletons and prominent pharmacological activities. , Strictosidine synthase (STR1, Figure ) is a gateway enzyme that conducts asymmetric Pictet–Spengler (P–S) condensation between tryptamine and secologanin to strictosidine for the biosynthesis of some 2000 MIAs. , Owing to the critical function of STR1 in the biosynthetic pathway of MIAs, it has been comprehensively studied in chemical biology following the disclosure of its 3D structure. − The P–S condensation catalyzed by STR1 is very attractive due to its advantages of high stereoselectivity and efficiency as well as mild reaction conditions. However, there are few examples demonstrating the chemoenzymatic use of STR1 to synthesize new alkaloids in the search for bioactive substances. , Previously, we reported the preparation of several MIAs by one-step syntheses starting from the STR1 reaction product strictosidine …”

mentioning

confidence: 99%

mentioning

confidence: 99%

Strictosidine Synthase Triggered Enantioselective Synthesis of N-Substituted (S)-3,14,18,19-Tetrahydroangustines as Novel Topoisomerase I Inhibitors

et al. 2017

View full text Add to dashboard Cite

Monoterpenoid indole alkaloids (MIAs) comprise an important class of molecules for drug discovery, and they have variant carbon skeletons with prominent bioactivities. For instance, in spite of limitations to their use, camptothecins are the only clinically approved topoisomerase I (Top1) inhibitors. The enzyme strictosidine synthase, which is key for MIA biosynthesis, was applied to the enantioselective preparation of three N-substituted (S)-3,14,18,19-tetrahydroangustine (THA) derivatives. These non-camptothecin MIAs were shown to have moderate in vitro HepG2 cytotoxicity and Top1 inhibition activities. The (S)-configured MIAs had stronger cytotoxicity and Top1 inhibition than their chemically synthesized (R)-enantiomers, which aligned with the results of molecular dynamics simulations. A series of N-substituted (S)-THAs were then chemoenzymatically synthesized to investigate structure-activity relationships. The most active analogue observed was the N-(2-Cl benzoyl)-substituted derivative (7i). Insight into the binding mode of 7i and a Top1-DNA covalent complex was investigated by molecular dynamics simulations, which will facilitate future efforts to optimize the Top1 inhibitory activities of non-camptothecin MIAs.

show abstract

Monoterpenoid Indole Alkaloids, CNS and Anticancer Drugs

Cited by 6 publications

References 95 publications

Antidepressant-like Effect of the Eburnamine-Type Molecule Vindeburnol in Rat and Mouse Models of Ultrasound-Induced Depression

Antidepressant-like Effect of the Eburnamine-Type Molecule Vindeburnol in Rat and Mouse Models of Ultrasound-Induced Depression

Stereoselective Total Syntheses of C18-Oxo Eburnamine-Vincamine Alkaloids

Strictosidine Synthase Triggered Enantioselective Synthesis of N-Substituted (S)-3,14,18,19-Tetrahydroangustines as Novel Topoisomerase I Inhibitors

Contact Info

Product

Resources

About