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Chemical Compound Review:

AC1L9LAK 2-[[4-[(2S)-2-(carboxyamino)- 2-[4-(3...

Synonyms: 1ph0

Chen, Q. et al., Petzer, J.P. et al., Pierson, M.E. et al., Thompson, J.E. et al., Krebs, F.C. et al., et al.

Marko, Habermeyer, Kemény, Weyand, Niederberger, Frank, Hofmann, Nomura, Yasukata, Narukawa, Uotani, Albright, Graciani, Han, Yue, Stein, Lai, Diamond, Dowling, Grimminger, Zhang, Behrens, Musselman, Bruckner, Zhang, Jiang, Hu, Higley, Dimeo, Rafalski, Mandlekar, Car, Yeleswaram, Stern, Copeland, Combs, Seitz, Trainor, Taub, Huang, Oliff, Krebs, Spanggaard, Thompson, Cubbon, Cummings, Wicker, Frankshun, Cunningham, Cameron, Meinke, Liverton, Weng, DeMartino, Grapperhaus, Mullins, Kozlowski, Mashuta,

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Disease relevance of COMPOUND 6

Interestingly, compound 6 displayed cytotoxic activity against a panel of human tumor cell lines but demonstrated negligible toxicity in vivo with no effect on the animals' hematology parameters [1].
Compound 6 has high affinity for the Lactobacillus casei enzyme (Ki = 0.75 microM, KI/Km - 0.23), which is 50 times stronger than that of the piperazinyl derivative 5 [2].
In addition to greater potency, compound 6 produces weight loss in rats when administered over nine consecutive days [3].
Compound 6 was found to have some activity against P388 lymphocytic leukemia [4].
Administration of these compounds resulted in tumor inhibition rates of 15.3-49.5% in mice bearing Lewis Lung Cancer, sarcoma180 or HepA tumor, with the highest value of 49.5% from compound 6 [5].

High impact information on COMPOUND 6

Compared with control, lead compound 6. demonstrated antagonist-reversible 55-fold lower accumulation in Pgp-expressing MDR cells [6].
Western blotting analysis demonstrated that compound 6 completely inhibited the expression of Bcl-2 gene, and compounds 1 and 8 produced a significant inhibition by 40 and 60%, respectively, compared to the control, while compound 7 did not alter the level of Bcl-2 [5].
Similarly, apoptosis induced by either a structurally distinct Bcl-2/Bcl-x(L) inhibitor (compound 6) or Bcl-2 antisense oligonucleotides was diminished by glutathione [7].
Compounds 1, 6, 7 and 8 induced apoptosis in HepG2 cells, with the highest apoptotic rate (55.34%) from compound 6 [5].
Following the discovery of the human histamine H4 receptor, a high throughput screen of our corporate compound collection identified compound 6 as a potential lead [8].

Chemical compound and disease context of COMPOUND 6

Although the 5-(1-aminoethyl)-2'-deoxyuridine.HI (5) was inactive against HSV-1 and HSV-2, the 5-(1-methoxyethyl) compound 6 was equiactive to 5-ethyl-2'-deoxyuridine (EDU) against both HSV-1 and HSV-2 and 7-fold and 12-fold less active against HCMV relative to EDU and ganciclovir, respectively [9].
Treatment with compound 6 of murine hepatoma cells containing a luciferase gene under the control of the antioxidant response element (ARE) from the mouse heme oxygenase (ho-1) gene elicits induction of luciferase activity, CD = 35.8 +/- 2.8 microM, somewhat greater than the potency than oltipraz itself [10].
Among the derivatives prepared, compound 6 with carbonate at the C-11,12 position was found to have potent antibacterial activities against erythromycin-resistant Staphylococcus aureus as well as other erythromycin-susceptible strains [11].
Compound 7 had a guanidino group inserted into compound 6; however, Compound 7 strongly inhibited hemolysis even in low-diluted serum, and suppressed Forssman systemic shock more potently than both FUT-175 and compound 6 [12].
Compound 6 was less toxic than doxorubicin at this efficacious dose because mice treated with compound 6 had no detectable changes in body weight or reticulocytes, a marker for marrow toxicity [13].

Biological context of COMPOUND 6

Compound (-)-6 inhibited CEM cell proliferation at a 50% inhibitory concentration of 27 micrograms/mL but proved not inhibitory to HEL cell proliferation and not toxic to E6SM, HeLa, Vero, and MDCK cells at concentrations up to 200 micrograms/mL [14].
Compound 6 was further evaluated for its ability to induce apoptosis in cancer cells [15].
Compound 6 has also shown good oral bioavailability and impressive pharmacokinetic characteristics [16].
Compound 6 was the most potent compound and had an IC(50) value of 4 microM in inhibition of cell growth using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay [15].
Both pharmacological ranking and QSAR considerations showed compound 6 as the optimum within the structural class under investigation [17].

Anatomical context of COMPOUND 6

Compound 6, 3-benzyl-8-methyl-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one, increased DOPA (L-3,4-dihydroxyphenylalanine) synthesis 84% in the hippocampus and 10% in the striatum of rat brain when dosed orally at 10 mg/kg [18].
The OMe-substituted N-oxides all showed greater metabolic stability than 2 in hypoxic AA8 cell cultures, and the 4-OMe compound 6 had improved activity in EMT6 multicellular spheroids suggesting that this metabolic stabilization may allow more efficient diffusion in tumor tissue [19].
Western blots of nuclear proteins isolated from Hepa 1c1c7 cells and probed with anti-Nrf2 indicate that as compared to vehicle DMSO, compound 6 stimulates nuclear translocation of Nrf2 from the cytosol [10].
Compound 6 exhibited significant cytotoxicity against cultured human hepatoma cells (SMMC-7721) and human acute promyelocytic leukemia cells (HL60) [20].
A low cytotoxicity of organometallic compound 6 against A431 and Capan-1 cancer cell lines was observed and this result is consistent with the low interaction with DNA observed in previous studies [21].

Associations of COMPOUND 6 with other chemical compounds

At pH 6.6, DV = 3.4 for the C5-deuteriated dihydroorotate (3), and DV = 2.3 for the C6-deuteriated compound (6) [22].
Compound 6 (Hpa(SO3H)-Nle-Gly-Trp-Nle-MeAsp-Phe-NH2), derived from moving the N-methyl group from Phe to Asp, decreased CCK-B affinity substantially without affecting CCK-A affinity, giving a compound with 6600-fold selectivity for CCK-A receptors [3].
Compound 7 shows blue fluorescence with little solvent dependence (lambda(emission) = 410 nm in THF, CH2Cl2, and hexane), whereas compound 6 shows a highly solvent-dependent emission wavelength (lambda(emission) = 583 nm in THF, lambda(emission) = 560 nm in CH2Cl2, and lambda(emission) = 450 nm in hexane) [23].
One of them, compound 6, exhibited an approximately 160-fold higher inhibition of [14C]glucose uptake by the GLUT1 transporter than glucose itself [24].
The solvent set of C6H6/CS2 gives 1:1:C6H6 compound 4 with unique charged anions, [CrIII(Cl4SQ)2(Cl4Cat)]-, while the other set, n-C6H12/CS2, affords 1:2 compound 6 including the two redox isomers, [CrIII(Cl4SQ)2(Cl4Cat)]- and [CrIII(Cl4SQ)3]0 [25].

Gene context of COMPOUND 6

Compound 6 inhibits Jak3 with K(I)=5 nM; it also inhibits Jak family members Tyk2 and Jak2 with IC(50)=1 nM and murine Jak1with IC(50)=15 nM [26].
Compound 6 showed interesting dual activation of PPAR alpha and PPAR gamma [16].
Compound 6 also blocks IL2 and IL4 dependent proliferation of CTLL cells and inhibits the phosphorylation of STAT5 (an in vivo substrate of the Jak family) as measured by Western blotting [26].
Of them, compound 6 clearly displayed the highest inhibitory effect on in-vitro TNF-alpha production from lipopolysaccharide (LPS)-stimulated RAW264.7 cells [27].
Compound 6 produces potent anorectic activity via the CCK-A receptor system [3].

Analytical, diagnostic and therapeutic context of COMPOUND 6

Compound 6 is a discrete supermolecule containing an asymmetric (C(2))(2)@Ag(13) cluster core capped by two [18]crown-6 ligands in mu(3)-eta(5) and mu(4)-eta(6) ligation modes [28].
After treatment with compound 6, DNA fragmentation was observed at a higher concentration range (> or = 50 microM), whereas incubation with 13 resulted in a marked DNA fragmentation already at 20 microM [29].
Complexes 1, 2, and 3 and compound 6 have been investigated by X-ray crystallography, and their structures are reported [30].
Furthermore, capillary electrophoresis assay implied that compound 6 could not only bind to TAR but also hinder the Tat-TAR interaction [31].
Against a panel of fast-growing mycobacteria and a standard ATCC strain of Staphylococcus aureus, compound 6 exhibited minimum inhibitory concentrations in the range of 64-128 microg/ml [32].

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