76958-67-3

Usage

Uses

Used in Pharmaceutical Industry:
HYPOTHEMYCIN is used as a research tool for studying the MEK-ERK signaling pathway and its role in various cellular processes. It is also used as a potential therapeutic agent for the treatment of diseases associated with the dysregulation of this pathway.
Used in Cancer Research:
HYPOTHEMYCIN is used as an inhibitor of MEK for investigating its role in the development and progression of cancer. It can be employed to study the effects of MEK inhibition on tumor growth, metastasis, and angiogenesis.
Used in Immunology Research:
HYPOTHEMYCIN is used as an inhibitor of TNFα production in LPS-stimulated macrophages, making it a valuable tool for studying the regulation of inflammatory responses and the role of TNFα in various immune-related diseases.
Used in Drug Discovery:
HYPOTHEMYCIN serves as a lead compound for the development of novel MEK inhibitors with improved potency, selectivity, and pharmacokinetic properties. It can be used as a starting point for the design and synthesis of new drugs targeting the MEK-ERK signaling pathway.

Biochem/physiol Actions

Hypothemycin, one of the highly oxygenated analogues in the group of 14-membered resorcylic acid lactones (RAL), has minor antifungal and cytotoxic activity and exhibits an in vitro anti-malarial activity with an IC50 of 2.2 μg/mL. Hypothemycin is also reported to selectively and irreversibly inhibit protein kinases that contain a conserved cysteine residue (Cys166) that is located within the ATP-binding domain. Though this group accounts for less then 10% of all identified kinases, there are several targets implicated in aberrant cellular proliferation such as ERKs, MEK, FMS-like tyrosine kinase protein (FLT), and platelet-derived growth factor receptors (PDGFR). In cell culture, hypothemycin displays potent cytotoxicity against cancer cell lines that are dependent on certain activating kinase mutations. Additionally, hypothemycin demonstrates significant tumor growth inhibition in at least three separate murine xenograft models. Hypothemycin also inhibits the production of several cytokines such as IL2, IL6, IFNγ, and TNFα.

References

1) Zhou et al. (1999), Resorcylic acid lactones: naturally occurring potent and selective inhibitors of MEK; J. Antibiot., 52 1086 2) Schirmer et al. (2006), Targeted covalent inactivation of protein kinases by resorcylic acid lactone polyketides; Proc. Natl. Acad. Sci. USA, 103 4234 3) Fukazawa et al. (2010), The resorcylic acid lactone hypothemycin selectively inhibits the mitogen-activated protein kinase kinase-extracellular signal-regulated kinase pathway in cells; Biol. Pharm. Bull., 33 168 4) Park et al. (2015), Hypothemycin inhibits tumor necrosis factor-α production by tristetraprolin-dependent down-regulation of mRNA stability in lipopolysaccharide-stimulated macrophages; Int. Immunopharmacol., 29 863

InChI:InChI=1/C19H22O8/c1-9-4-3-5-12(20)18-15(27-18)8-14(22)17(23)11-6-10(25-2)7-13(21)16(11)19(24)26-9/h3,5-7,9,14-15,17-18,21-23H,4,8H2,1-2H3/b5-3-/t9?,14-,15+,17-,18-/m0/s1

Upstream product

• 253863-19-3 LL-Z₁₆₄₀-2 
• 460348-38-3 2-Hydroxy-6-((E)-3-{(4S,5S)-5-[(Z)-(R)-5-hydroxy-1-(4-methoxy-benzyloxy)-hex-2-enyl]-2,2-dimethyl-[1,3]dioxolan-4-yl}-propenyl)-4-methoxy-benzoic acid methyl ester 
• 460348-31-6 2-Bromo-6-hydroxy-4-methoxy-benzoic acid (Z)-(S)-5-((4S,5S)-2,2-dimethyl-5-prop-2-ynyl-[1,3]dioxolan-4-yl)-5-(4-methoxy-benzyloxy)-1-methyl-pent-3-enyl ester 
• 460358-62-7 (2E,11Z)-(5S,9S,14S)-18-Hydroxy-20-methoxy-10-(4-methoxy-benzyloxy)-7,7,14-trimethyl-6,8,15-trioxa-tricyclo[15.4.0.0^5,9]henicosa-1⁽²¹⁾,2,11,17,19-pentaen-16-one 
• 460358-77-4 (2E,11Z)-(5S,9R,10R,14S)-10,18-Dihydroxy-20-methoxy-7,7,14-trimethyl-6,8,15-trioxa-tricyclo[15.4.0.0^5,9]henicosa-1⁽²¹⁾,2,11,17,19-pentaen-16-one 
• 66018-39-1 FR₂₆₄₇₄₄ 
• 460358-69-4 (2E,11Z)-(5S,9R,14S)-10,18-Dihydroxy-20-methoxy-7,7,14-trimethyl-6,8,15-trioxa-tricyclo[15.4.0.0^5,9]henicosa-1⁽²¹⁾,2,11,17,19-pentaen-16-one 

Relevant academic research and scientific papers

Divergent syntheses of resorcylic acid lactones: L-783277, LL-Z1640-2, and hypothemycin

The resorcylic acid lactones (RAL) are endowed with diverse biological activity ranging from transcription factor modulators (zearalenone and zearalenol) to HSP90 inhibitors (radicicol and pochonin D) and reversible (aigialomycin D) as well as irreversibl

Convergent stereospecific synthesis of LL-Z1640-2 (or C292), hypothemycin and related macrolides. Part 2

The total synthesis of C292 (or LL-Z1640-2) and hypothemycin has been achieved. The 14-membered ring formation was achieved either via an intramolecular Suzuki coupling or much more efficiently via a Mitsunobu macrolactonisation. Reaction conditions were