3-Methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol: the Importance of Functional Groups for Antiparkinsonian Activity

Ardashov, Oleg V.; Павлова, А. В.; Корчагина, Д. В.; Волчо, К. П.; Tolstikova, Tat’ yana G.; Salakhutdinov, N. F.

doi:10.2174/1573406411309050013

Cited by 11 publications

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“…[10][11][12] We synthesized and tested in vivo a number of derivatives, including all eight stereoisomers of compound 1. 13 It was found that all of the four functional groups of 1 are needed for the compound to exhibit anti-PD activity. Among N-, O-, S-and C-derivatives at the C9 position of diol 1, compounds 2 and 3 with butyl or propylthio substituents exhibited a high activity.…”

Section: Introductionmentioning

confidence: 99%

“…We have previously discovered a small low-toxicity molecule (1 R ,2 R ,6 S )-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol 1 (Figure ) that can potently alleviate motor symptoms in rodent models of PD. − We synthesized and tested in vivo a number of derivatives, including all eight stereoisomers of compound 1 . It was found that all four functional groups of 1 are needed for the compound to exhibit anti-PD activity . Among N-, O-, S-, and C-derivatives at the C9 position of diol 1 , compounds 2 and 3 with butyl or propylthio substituents exhibited a high activity …”

Section: Introductionmentioning

confidence: 99%

“…1 H NMR (500 MHz, CDCl3/CD3OD): δ 1.30 (s, C 9 H3), 1.75 (m, C 10 H3, all J ≤ 2.5 Hz), 2.01 (dddq, H 5e , 2 J = 17.6, J5e,6a 5.6, J5e,4 = 5.3, J5e,10 = 1.6 Hz), 2.12 (ddd, H 6a , J6a,5a = 11.3, J6a,5e = 5.6, J6a,1e = 1.8 Hz), 2.26 (dddqd, H 5a , 2 J = 17.6, J5a,6a = 11.3, J5a,4 = J5a,10 = 2.5, J5a,2e = 1.3 Hz), 3.35 (dd, H 8 , 2 J = 10.2, J8,9 = 0.6 Hz), 3.39 (d, H 8' , 2 J = 10.2 Hz), 3.64 (br. d, H 2e , J2e,1e = 2.7 Hz), 4.10 (dd, H 1e , J1e,2e = 2.7, J1e,6a = 1.8 Hz), 5.62 (ddq, H4 , J4,5e = 5.3, J4,5a = 2.5, J4,10 = 1.5 Hz) 13. C NMR (125 MHz, CDCl3/CD3OD): δ 70.40 (d, C 1 ), 71.99 (d, C 2 ), 130.85 (s, C 3 ), 125.18 (d, C 4 ), 21.66 (t, C 5 ), 36.17 (d, C 6 ), 73.04 (s, C 7 ), 17.79 (t, C 8 ), 25.19 (q, C 9 ), 20.73 (q, C 10 ).…”

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A Novel Small Molecule Supports the Survival of Cultured Dopamine Neurons and May Restore the Dopaminergic Innervation of the Brain in the MPTP Mouse Model of Parkinson’s Disease

Ardashov

Павлова

Mahato

et al. 2019

ACS Chem. Neurosci.

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We previously showed that monoterpenoid (1R,2R,6S)-3-methyl-6-(prop-1-en-2yl)cyclohex-3-ene-1,2-diol 1 alleviates motor manifestations of Parkinson's disease in animal models. In the present study, we designed and synthesized monoepoxides of (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol 1 and evaluated their biological activity in the MPTP mouse model of Parkinson's disease. We also assessed the ability of these compounds to penetrate the blood brain barrier (BBB). According to these data, we choose epoxide 4, which potently restored locomotor activity in MPTP-treated mice and penetrated the BBB with high efficacy, to further explore the potential mechanism of action. Epoxide 4 was found to robustly promote the survival of cultured dopamine neurons, protect dopamine neurons from toxin-induced degeneration and trigger the mitogen-activated protein kinase (MAPK) signaling cascade in cells of neuronal 2 origin. Meanwhile, neither survival-promoting effect nor MAPK activation was observed in nonneuronal cells treated with epoxide 4. In the MPTP mice model of Parkinson's disease, compound 4 increased the density of fibers expressing the key enzyme of dopamine synthesis, tyrosine hydroxylase. Taken together, these data indicate that epoxide 4 can be a promising compound for further development not only as symptomatic treatment but also as a disease-modifying drug to treat Parkinson's disease.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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A Novel Small Molecule Supports the Survival of Cultured Dopamine Neurons and May Restore the Dopaminergic Innervation of the Brain in the MPTP Mouse Model of Parkinson’s Disease

Ardashov

Павлова

Mahato

et al. 2019

ACS Chem. Neurosci.

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“…The absolute configuration of 1 affected its anti-Parkinson's activity [1]. It was important to include all functional groups (double bonds and hydroxyls) in the molecule [3]. Metabolism studies represent a key phase of pharmacokinetic investigations.…”

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“…Very effective methods for adding and removing pyranyl protection using In(OTf) 3 [17] and (NH 4 ) 2 Ce(NO 3 ) 6 (CAN) [18] as catalysts were described. Use of In(OTf) 3 , CAN, or PPTS in various solvents to remove THP from stereomers 9 was accompanied by secondary and/or side reactions and formed complicated product mixtures.…”

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Synthesis of 10-Carbonyl and 10-Carboxylic Derivatives of para-Mentha-1,8-Diene-5,6-Diol

et al. 2015

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The synthesis of 10-carbonyl and 10-carboxylic derivatives of para-mentha-1,8-diene-5,6-diol (1) that exhibited high anti-Parkinson's activity was described. The synthesis of these compounds was an important programmatic component in a study of the metabolism of 1.Our previous discovery [1, 2] that (4S,5R,6R)-para-mentha-1,8-diene-5,6-diol (1) exhibited high anti-Parkinson's activity stimulated further studies of it. The absolute configuration of 1 affected its anti-Parkinson's activity [1]. It was important to include all functional groups (double bonds and hydroxyls) in the molecule [3]. Metabolism studies represent a key phase of pharmacokinetic investigations. As a rule, mass spectra of monoterpenoids are very difficult to relate reliably to their structures without mass spectrometric data of the pure compounds, which makes it necessary to synthesize them.According to literature data on the metabolism of para-menthane monoterpenoids [4][5][6][7], the formation of products from methyl hydroxylation and further oxidation to carbonyl compounds were expected. We synthesized earlier hydroxyderivatives 2 [8] and 3 [9]. The methods for synthesizing these and other similar alcohols were recently reviewed by us in detail [10].The goal of the present work was to synthesize 10-carbonyl and 10-carboxylic derivatives of 1. The first task was to prepare 2-[(1S,5R,6R)-5,6-dihydroxy-4-methylcyclohex-3-enyl]acrylaldehyde (3). The simplest approach seemed to involve oxidation of triol 2. However, its reaction with MnO 2 formed reaction mixtures with <30% of target aldehyde 3 according to PMR and GC-MS data.We used bromide 4 as a key intermediate in the synthesis of triol 2 [8]. Also, bromides are known to be capable of transforming into the corresponding aldehydes via alkylation of nitro compounds followed by Nef hydrolysis [11,12] or Kornblum oxidation by 14]. However, instead of the expected reaction with EtNO 2 , 4 underwent an intramolecular heterocyclization to form bicyclic product 5 in quantitative yield (Scheme 1). We prepared previously 5 in 15% yield via the reaction of 4 with n-BuLi [8]. Thus, the newly found version for performing the intramolecular cyclization turned out to be much more effective. Kornblum oxidation of 5 via reaction with DMSO in CCl 4 formed a complicated product mixture with total contents of identified 3 and 5 of <7%. 1) N. N. VorozhtsovOH OH 1 3 5 9 7 OH OH OH OH OH O 1 2 3

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The First Synthesis of (4S,5R,6R)‐5,6‐Dihydroxy‐4‐(prop‐1‐en‐2‐yl)cyclohex‐1‐ene‐1‐carboxylic Acid

Ardashov

Demidova

Корчагина

et al. 2015

Helvetica Chimica Acta

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irogova 2, RU-630090 Novosibirsk c )Boreskov Institute of Catalysis,p r. Lavrentieva, 5, RU-630090 Novosibirsk Ap utative acid metabolite of an ovel highly effective antiparkinsonian agent, (4S,5R,6R)-5,6dihydroxy-4-(prop-1-en-2-yl)cyclohex-1-ene-1-carboxylic acid (5), was synthesizedf or the first time. Several synthetic approaches based on different transformations of O-bearing monoterpenoids of the pinane and p-menthanes eries were developed and tested in the course of the study.A cid 5 was synthesized starting from ac ommercially available monoterpenoid, (À)-verbenone,i natotal yield of 4.4% over eightsteps. Helv eticaChimica Acta -V ol. 98 (2015)1 443 Scheme 1. Syntheses of Triol 3 and Aldehyde 6 Helv eticaChimica Acta -V ol. 98 (2015) 1444 Scheme 2. Transformations of 6 and Structureof11 Scheme3. Synthesisa nd Rearrangements of (À)-cis-Verbenol Epoxide (12) Helv eticaChimica Acta -V ol. 98 (2015)1 445 Scheme 4. Synthesis of 19 Helv eticaChimica Acta -V ol. 98 (2015)1 447 Scheme 6. Possible Mechanism of the Formation of 24 Scheme 7. Transformationso f 22

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3-Methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol: the Importance of Functional Groups for Antiparkinsonian Activity

Cited by 11 publications

References 0 publications

A Novel Small Molecule Supports the Survival of Cultured Dopamine Neurons and May Restore the Dopaminergic Innervation of the Brain in the MPTP Mouse Model of Parkinson’s Disease

A Novel Small Molecule Supports the Survival of Cultured Dopamine Neurons and May Restore the Dopaminergic Innervation of the Brain in the MPTP Mouse Model of Parkinson’s Disease

Synthesis of 10-Carbonyl and 10-Carboxylic Derivatives of para-Mentha-1,8-Diene-5,6-Diol

The First Synthesis of (4S,5R,6R)‐5,6‐Dihydroxy‐4‐(prop‐1‐en‐2‐yl)cyclohex‐1‐ene‐1‐carboxylic Acid

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