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Synthesis and discovery of novel hexacyclic cage compounds as inhibitors of acetylcholinesterase

Suresh Kumar R, Ashraf Ali M, Osman H, Ismail R, Choon TS, Yoon YK, et al.

Bioorg Med Chem Lett, 2011 Jul 1;21(13):3997-4000.
PMID: 21621414 DOI: 10.1016/j.bmcl.2011.05.003

Hexacyclic derivatives share vital pharmacological properties, considered useful in Alzheimer's disease. The aim of this study was synthesis and its evaluation for acetyl cholinesterase inhibitory activity of novel hexacyclic analogues. Compound 4f, showed potent inhibitory activity against acetyl cholinesterase enzyme with IC(50) 0.72 μmol/L.

Matched MeSH terms: Heterocyclic Compounds with 4 or More Rings/pharmacology
Try to Remember: Interplay between Memory and Substance Use Disorder

Mohamed RMP, Kumar J, Yap E, Mohamed IN, Sidi H, Adam RL, et al.

Curr Drug Targets, 2019;20(2):158-165.
PMID: 28641520 DOI: 10.2174/1389450118666170622092824

Memories associated with substance use disorders, or substance-associated cues increase the likelihood of craving and relapse during abstinence. There is a growing consensus that manipulation of synaptic plasticity may reduce the strength of substance abuse-related memories. On the biological front, there are new insights that suggest memories associated with substance use disorder may follow unique neurobiological pathways that render them more accessible to pharmacological intervention. In parallel to this, research in neurochemistry has identified several potential candidate molecules that could influence the formation and maintenance of long-term memory. Drugs that target these molecules (blebbistatin, isradipine and zeta inhibitory peptide) have shown promise at the preclinical stage. In this review, we shall provide an overview of the evolving understanding on the biochemical mechanisms involved in memory formation and expound on the premise that substance use disorder is a learning disorder.

Matched MeSH terms: Heterocyclic Compounds with 4 or More Rings/pharmacology
Fulltext Efficacy of carbazole alkaloids, essential oil and extract of Murraya koenigii in enhancing subcutaneous wound healing in rats

Nagappan T, Segaran TC, Wahid ME, Ramasamy P, Vairappan CS

Molecules, 2012 Dec 05;17(12):14449-63.
PMID: 23519245 DOI: 10.3390/molecules171214449

The traditional use of Murraya koenigii as Asian folk medicine prompted us to investigate its wound healing ability. Three carbazole alkaloids (mahanine (1), mahanimbicine (2), mahanimbine (3)), essential oil and ethanol extract of Murraya koenigii were investigated for their efficacy in healing subcutaneous wounds. Topical application of the three alkaloids, essential oil and crude extract on 8 mm wounds created on the dorsal skin of rats was monitored for 18 days. Wound contraction rate and epithelialization duration were calculated, while wound granulation and collagen deposition were evaluated via histological method. Wound contraction rates were obvious by day 4 for the group treated with extract (19.25%) and the group treated with mahanimbicine (2) (12.60%), while complete epithelialization was achieved on day 18 for all treatment groups. Wounds treated with mahanimbicine (2) (88.54%) and extract of M. koenigii (91.78%) showed the highest rate of collagen deposition with well-organized collagen bands, formation of fibroblasts, hair follicle buds and with reduced inflammatory cells compared to wounds treated with mahanine (1), mahanimbine (3) and essential oil. The study revealed the potential of mahanimbicine (2) and crude extract of M. koenigii in facilitation and acceleration of wound healing.

Matched MeSH terms: Heterocyclic Compounds with 4 or More Rings/pharmacology
Paradoxical pinpoint pupils with asenapine

Gill JS, Jambunathan S, Wong S, Wong A

Asia Pac Psychiatry, 2015 Jun;7(2):230.
PMID: 25923587 DOI: 10.1111/appy.12171
Matched MeSH terms: Heterocyclic Compounds with 4 or More Rings/pharmacology
Biologically active vallesamine, strychnan, and rhazinilam alkaloids from Alstonia: Pneumatophorine, a nor-secovallesamine with unusual incorporation of a 3-ethylpyridine moiety

Lim JL, Sim KS, Yong KT, Loong BJ, Ting KN, Lim SH, et al.

Phytochemistry, 2015 Sep;117:317-24.
PMID: 26125941 DOI: 10.1016/j.phytochem.2015.06.024

Four alkaloids comprising two vallesamine, one strychnan, and one pyranopyridine alkaloid, in addition to 32 other known alkaloids were isolated from two Malayan Alstonia species, Alstonia pneumatophora and Alstonia rostrata. The structures of these alkaloids were determined using NMR and MS analyses, and in one instance, confirmed by X-ray diffraction analysis. The nor-6,7-secovallesamine alkaloid, pneumatophorine, is notable for an unusual incorporation of a 3-ethylpyridine moiety in a monoterpenoid indole. The rhazinilam-type alkaloids (rhazinicine, nor-rhazinicine, rhazinal, and rhazinilam) showed strong cytotoxicity toward human KB, HCT-116, MDA-MB-231, and MRC-5 cells, while pneumatophorine, the uleine alkaloid undulifoline, and the strychnan alkaloids, N4-demethylalstogustine and echitamidine, induced concentration dependent relaxation in phenylephrine-precontracted rat aortic rings.

Matched MeSH terms: Heterocyclic Compounds with 4 or More Rings/pharmacology
Alstoscholactine and Alstolaxepine, Monoterpenoid Indole Alkaloids with γ-Lactone-Bridged Cycloheptane and Oxepane Moieties from Alstonia scholaris

Krishnan P, Lee FK, Chong KW, Mai CW, Muhamad A, Lim SH, et al.

Org. Lett., 2018 12 21;20(24):8014-8018.
PMID: 30543301 DOI: 10.1021/acs.orglett.8b03592

Two new monoterpenoid indole alkaloids, alstoscholactine (1) and alstolaxepine (2), were isolated from Alstonia scholaris. Compound 1 represents a rearranged stemmadenine alkaloid with an unprecedented C-6-C-19 connectivity, whereas compound 2 represents a 6,7- seco-angustilobine B-type alkaloid incorporating a rare γ-lactone-bridged oxepane ring system. Their structures and absolute configurations were determined by spectroscopic analyses. Compound 1 was successfully semisynthesized from 19 E-vallesamine. Compound 2 induced marked vasorelaxation in rat isolated aortic rings precontracted with phenylephrine.

Matched MeSH terms: Heterocyclic Compounds with 4 or More Rings/pharmacology*
The effects of NLRP3 inflammasome inhibition by MCC950 on LPS-induced pancreatic adenocarcinoma inflammation

Yaw ACK, Chan EWL, Yap JKY, Mai CW

J Cancer Res Clin Oncol, 2020 Sep;146(9):2219-2229.
PMID: 32507974 DOI: 10.1007/s00432-020-03274-y

PURPOSE: Pancreatic cancer is a lethal form of cancer that can be triggered by prolonged or acute inflammation of the pancreas. Inflammation have been shown to be regulated by a group of key protein molecules known as the inflammasomes. The NLRP3 inflammasome is the most studied inflammasome and have been strongly implicated to regulate cancer cell proliferation. Therefore, this study aimed to examine the regulation of NLRP3 inflammasome under LPS-induced inflammation and its role in modulating cell proliferation in a panel of pancreatic cancer cells.
METHODS: The effects of LPS-induced NLRP3 activation in the presence or absence of MCC950, NLRP3-specific inhibitor, was tested on a panel of three pancreatic cancer cell lines (SW1990, PANC1 and Panc10.05). Western blotting, cell viability kits and ELISA kits were used to examine the effects of LPS-induced NLRP3 activation and inhibition by MCC950 on NLRP3 expression, cell viability, caspase-1 activity and cytokine IL-1β, respectively.
RESULTS: LPS-induced inflammation in the presence of ATP activates NLRP3 that subsequently increases pancreatic cancer cell proliferation by increasing caspase-1 activity leading to overall production of IL-1β. The inhibition of the NLRP3 inflammasome activation via the specific NLRP3 antagonist MCC950 was able to reduce the cell viability of pancreatic cancer cells. However, the efficacy of MCC950 varies between cell types which is most probably due to the difference in ASC expressions which have a different role in inflammasome activation.
CONCLUSION: There is a dynamic interaction between inflammasome that regulates inflammasome-mediated inflammation in pancreatic adenocarcinoma cells.

Matched MeSH terms: Heterocyclic Compounds with 4 or More Rings/pharmacology*
A Bis-benzopyrroloisoquinoline Alkaloid Incorporating a Cyclobutane Core and a Chlorophenanthroindolizidine Alkaloid with Cytotoxic Activity from Ficus fistulosa var. tengerensis

Al-Khdhairawi AAQ, Krishnan P, Mai CW, Chung FF, Leong CO, Yong KT, et al.

J Nat Prod, 2017 10 27;80(10):2734-2740.
PMID: 28926237 DOI: 10.1021/acs.jnatprod.7b00500

Tengerensine (1), isolated as a racemate and constituted from a pair of bis-benzopyrroloisoquinoline enantiomers, and tengechlorenine (2), purified as a scalemic mixture and constituted from a pair of chlorinated phenanthroindolizidine enantiomers, were isolated from the leaves of Ficus fistulosa var. tengerensis, along with three other known alkaloids. The structures of 1 and 2 were determined by spectroscopic data interpretation and X-ray diffraction analysis. The enantiomers of 1 were separated by chiral-phase HPLC, and the absolute configurations of (+)-1 and (-)-1 were established via experimental and calculated ECD data. Compound 1 is notable in being a rare unsymmetrical cyclobutane adduct and is the first example of a dimeric benzopyrroloisoquinoline alkaloid, while compound 2 represents the first naturally occurring halogenated phenanthroindolizidine alkaloid. Compound (+)-1 displayed a selective in vitro cytotoxic effect against MDA-MB-468 cells (IC50 7.4 μM), while compound 2 showed pronounced in vitro cytotoxic activity against all three breast cancer cell lines tested (MDA-MB-468, MDA-MB-231, and MCF7; IC50 values of 0.038-0.91 μM).

Matched MeSH terms: Heterocyclic Compounds with 4 or More Rings/pharmacology*
Fulltext Antiproliferative activity of xanthones isolated from Artocarpus obtusus

Hashim NM, Rahmani M, Ee GC, Sukari MA, Yahayu M, Oktima W, et al.

J Biomed Biotechnol, 2012;2012:130627.
PMID: 21960741 DOI: 10.1155/2012/130627

An investigation of the chemical constituents in Artocarpus obtusus species led to the isolation of three new xanthones, pyranocycloartobiloxanthone A (1), dihydroartoindonesianin C (2), and pyranocycloartobiloxanthone B (3). The compounds were subjected to antiproliferative assay against human promyelocytic leukemia (HL60), human chronic myeloid leukemia (K562), and human estrogen receptor (ER+) positive breast cancer (MCF7) cell lines. Pyranocycloartobiloxanthone A (1) consistently showed strong cytotoxic activity against the three cell lines compared to the other two with IC(50) values of 0.5, 2.0 and 5.0 μg/mL, respectively. Compound (1) was also observed to exert antiproliferative activity and apoptotic promoter towards HL60 and MCF7 cell lines at respective IC(50) values. The compound (1) was not toxic towards normal cell lines human nontumorigenic breast cell line (MCF10A) and human peripheral blood mononuclear cells (PBMCs) with IC(50) values of more than 30 μg/mL.

Matched MeSH terms: Heterocyclic Compounds with 4 or More Rings/pharmacology*