Cyclipostin A
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| Category | Enzyme inhibitors |
| Catalog number | BBF-01104 |
| CAS | |
| Molecular Weight | 460.54 |
| Molecular Formula | C23H41O7P |
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Description
It is produced by the strain of Streptomyces sp. DSM 13381. It is a hormone-sensitive lipase (HSL) inhibitor with a MIC of 20 nmol/L against HSL in rats.
Specification
| IUPAC Name | (8aR)-3-(12-hydroxyhexadecoxy)-5-methyl-3-oxo-8,8a-dihydro-1H-furo[3,4-e][1,3,2]dioxaphosphepin-6-one |
| Canonical SMILES | CCCCC(CCCCCCCCCCCOP1(=O)OCC2COC(=O)C2=C(O1)C)O |
| InChI | InChI=1S/C23H41O7P/c1-3-4-14-21(24)15-12-10-8-6-5-7-9-11-13-16-28-31(26)29-18-20-17-27-23(25)22(20)19(2)30-31/h20-21,24H,3-18H2,1-2H3/t20-,21?,31?/m1/s1 |
| InChI Key | JGTUCPMGHURLJI-FRMQRXHYSA-N |
Reference Reading
1. Cyclophostin and Cyclipostins analogues, new promising molecules to treat mycobacterial-related diseases
Phuong Chi Nguyen, Abdeldjalil Madani, Pierre Santucci, Benjamin P Martin, Rishi R Paudel, Sandrine Delattre, Jean-Louis Herrmann, Christopher D Spilling, Laurent Kremer, Stéphane Canaan, Jean-François Cavalier Int J Antimicrob Agents. 2018 Apr;51(4):651-654. doi: 10.1016/j.ijantimicag.2017.12.001. Epub 2017 Dec 11.
The progression of mycobacterial diseases requires the development of new therapeutics. This study evaluated the efficacy and selectivity of a panel of Cyclophostin and Cyclipostins analogues (CyCs) against various bacteria and mycobacteria. The activity 26 CyCs was first assayed by the agar plate method. Compounds exhibiting 50-100% growth inhibition were then selected to determine their minimum inhibitory concentrations (MICs) by the resazurin microtiter assay (REMA). The best drug candidate was further tested against clinical mycobacterial isolates and bacteria responsible for nosocomial infections, including 6 Gram-negative bacteria, 5 Gram-positive bacteria, 29 rapid-growing mycobacteria belonging to the Mycobacterium chelonae-abscessus clade and 3 slow-growing mycobacteria (Mycobacterium marinum, Mycobacterium bovis BCG and Mycobacterium tuberculosis). Among the 26 CyCs tested, 10 were active and their inhibitory activity was exclusively restricted to mycobacteria. The best candidate (CyC17) was further tested against 26 clinical strains and showed high selectivity for mycobacteria, with MICs (<2-40 µg/mL) comparable with those of most classical antimicrobials used to treat M. abscessus infections. Together, these results support the fact that such CyCs represent a new family of potent and selective inhibitors against mycobacteria. This is of particular interest for future chemotherapeutic developments against mycobacterial-associated infections, especially against M. abscessus, the most drug-resistant mycobacterial species.
2. Rat hormone sensitive lipase inhibition by cyclipostins and their analogs
Elena Vasilieva, Supratik Dutta, Raj K Malla, Benjamin P Martin, Christopher D Spilling, Cynthia M Dupureur Bioorg Med Chem. 2015 Mar 1;23(5):944-52. doi: 10.1016/j.bmc.2015.01.028. Epub 2015 Jan 22.
Cyclipostins are bicyclic lipophilic phosphate natural products. We report here that synthesized individual diastereomers of cyclipostins P and R have nanomolar IC50s toward hormone sensitive lipase (HSL). The less potent diastereomers of these compounds have 10-fold weaker IC50s. The monocyclic phosphate analog of cyclipostin P is nearly as potent as the bicyclic natural product. Bicyclic phosphonate analogs of both cyclipostins exhibit IC50s similar to those of the weaker diastereomer phosphates (about 400nM). The monocyclic phosphonate analog of cyclipostin P has similar potency. A series of monocyclic phosphonate analogs in which a hydrophobic tail extends from the lactone side of the ring are considerably poorer inhibitors, with IC50s around 50μM. Finally cyclophostin, a related natural product inhibitor of acetylcholinesterase (AChE) that lacks the hydrocarbon tail of cyclipostins, is not active against HSL. These results indicate a critical SAR for these compounds, the hydrophobic tail. The smaller lactone ring is not critical to activity, a similarity shared with cyclophostin and AChE. The HSL kinetics of inhibition for the cyclipostin P trans diastereomer were examined in detail. The reaction is irreversible with a KI of 40nM and a rate constant for inactivation of 0.2min(-1). These results are similar to those observed for cyclophostin and AChE.
3. Synthesis and kinetic evaluation of cyclophostin and cyclipostins phosphonate analogs as selective and potent inhibitors of microbial lipases
Vanessa Point, Raj K Malla, Sadia Diomande, Benjamin P Martin, Vincent Delorme, Frederic Carriere, Stephane Canaan, Nigam P Rath, Christopher D Spilling, Jean-François Cavalier J Med Chem. 2012 Nov 26;55(22):10204-19. doi: 10.1021/jm301216x. Epub 2012 Nov 7.
A new series of customizable diastereomeric cis- and trans-monocyclic enol-phosphonate analogs to Cyclophostin and Cyclipostins were synthesized. Their potencies and mechanisms of inhibition toward six representative lipolytic enzymes belonging to distinct lipase families were examined. With mammalian gastric and pancreatic lipases no inhibition occurred with any of the compounds tested. Conversely, Fusarium solani Cutinase and lipases from Mycobacterium tuberculosis (Rv0183 and LipY) were all fully inactivated. The best inhibitors displayed a cis conformation (H and OMe) and exhibited higher inhibitory activities than the lipase inhibitor Orlistat toward the same enzymes. Our results have revealed that chemical group at the γ-carbon of the phosphonate ring strongly impacts the inhibitory efficiency, leading to a significant improvement in selectivity toward a target lipase over another. The powerful and selective inhibition of microbial (fungal and mycobacterial) lipases suggests that these seven-membered monocyclic enol-phosphonates should provide useful leads for the development of novel and highly selective antimicrobial agents.
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Bio Calculators
* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C1V1 = C2V2
* Total Molecular Weight:
g/mol
Tip: Chemical formula is case sensitive. C22H30N4O √ c22h30n40 ╳
