Chemicals & Small Molecules

FTY720P is the bioactive form of the novel immunosuppressive drug fingolimod (FTY720). FTY720 is converted to FTY720P by sphingosine kinase and the (S)-isomer acts as an agonist to four S1P receptors (S1P1 3 4 5) with IC50s of 2.1 5.9 23 and 2.2 nM respectively. The R isomer binds with 5-10 fold lower affinity. FTY720P improves the survival of neonatal rat oligodendrocytes regulates oligodendrocyte progenitor cells differentiation promotes astrocyte migration via extracellular signal-regulated kinase (ERK) signaling. Recently published results indicate involvement of FTY720P in complete viral clearance of persistent infection caused by clone 13 of lymphotic choriomeningitis virus (LCMV).Publications Powered by Bioz See more details on Bioz1. Bucki R. et al. (2010). "Plasma gelsolin modulates cellular response to sphingosine 1-phosphate." Am J Physiol Cell Physiol 299(6): C1516-1523.2. Gu Y. et al. (2011). "Epithelial cell extrusion requires the sphingosine-1-phosphate receptor

To date six types of receptors LPA1-6 have been identified and are responsible for most of the biological activities of LPA. Recent studies on gene targeting in mice and family diseases of these receptors revealed that LPA is involved in various patho-physiological states. LPA antagonists have attracted considerable attention and numerous small molcules having LPA antagonistic activity have been reported. Ki16425 is an antagonist of LPA1 and LPA3 receptors with moderate activity against LPA2.References: Powered by Bioz See more details on Bioz1. Hideo Ohta et al “Ki16425 a Subtype-Selective Antagonist for EDG-Family Lysophosphatidic Acid Receptors” Molecular Pharmacology 2003 166(4) 994-10052. Jing Zhao et al “Lysophosphatidic Acid Receptor 1 antagonist Ki16425 Blunts Abdominal and Systemic Inflammation in a Mouse Model of Peritoneal Sepsis” Translational Research 2015 166(1) 80–88

9-tert-Butyl Doxycycline (9TB) is a Tet On/Off system agonist capable of activating and acting as an inducer for the tetracycline-transactivator (tTA) and reverse tTA (rtTA) and tTA-responsive promoters (Ptets) herein known as the Tet switch. The compound is able to activate the Tet switch with approximately 10-fold greater efficacy especially in lipophilic environments such as the brain and lung and other similar biocompartments. 9TB is freely soluble in water and can be administered IV IP and in the drinking water of experimental animals allowing for ready dosing. 9TB also has found use in studying hypoxia-regulated gene expression on cell survival using the tetracycline-inducible (tet-on) system where exposure to the inducing ligand doxycycline (dox) inhibited caspase-3 cleavage in mitochondria in Publications Powered by Bioz See more details on Bioz1) Zhu P. et al. “Silencing and Un-silencing of Tetracycline-Controlled Genes in Neurons” PLoS ONE. 2007; 2(6): e533.2)

Chemically modified tetracyclines show activity in mammalian cell pathways and diseases related to cancer inflammation and neurodegenerative pathways. 4-Dedimethylaminosancycline (CMT-3 or COL-3) acts as matrix metalloproteinase (MT-MMP) inhibitor. It has been studied in disorders of collagen destruction excessive TNF activity excessive nitric oxide activity excessive IL-1 activity excessiuve activity of elastase bone loss protein degradation muscle wasting collagen glycosylation phospholipase A2 activity. In addition CMT-3 has been investigated for the treatment of aneurysms ulcerations periodontal disease diabetes scleroderma progeria cancer and diseases of bone marrow function and thrombocytopenia.Alternate names: CMT-3 COL-3 COL-3 Compound Incyclinide NSC-683551

5-Ketoclomazone inhibits 1-deoxy-D-xylulose 5-phosphate (DXP) synthase the first enzyme of the MEP pathway (non-mevalonate pathway) of isoprenoid biosynthesis.References1) Y. Matsue H. Mizuno T. Tomita et al. "The herbicide ketoclomazone inhibits 1-deoxy-D-xylulose 5-phosphate synthase in the 2-C-methyl-D-erythritol 4-phosphate pathway and shows antibacterial activity against Haemophilus influenzae" J. Antibiotics (2010) 63 583-588. DOI: 10.1038/ja.2010.100

The non-mevalonate or MEP pathway for isoprenoid biosynthesis is essential in gram-negative some gram-positive bacteria plants and protozoa making it an attractive pathway to target for antibiotics since mammals use the mevalonate pathway to synthesize isoprenoids. IspF is the fourth step in the pathway and converts diphosphocytidyl-2-methylerythritol 2-phosphate into 2-methylerythritol 2 4-cyclodiphosphate (cMEPP). IspF inhibitor 1 (compound 3 in Geist et al.) has low micromolar activity (IC50 = 6.1-32 μM) against the recombinant enzymes and inhibits the growth of P. falciparum in a red blood cell assay.ReferenceJ.G. Geist et al “Thiazolopyrimidine Inhibitors of 2-Methylerythritol 2 4-Cyclodiphosphate Synthase (IspF) from Mycobacteriumtuberculosis and Plasmodium falciparum” ChemMedChem 2010 5 1092-1101.

Compounds that target isoprenoid biosynthesis in plasmodium falciparum could be a welcome addition to malaria chemotherapy since the methylerythritol phosphate (MEP) pathway used by the parasite is not present in humans. MMV008138 targets the apicoplast of P. falciparum and that its target in the MEP pathway differs from that of Fosmidomycin. The active stereoisomer of MMV008138 was (1R 3S)-configured which was found to be crucial for inhibition of the parasite growth as a MEP pathway-targeting antimalarial agent. Recently some researchers have claimed that they identified the molecular target of MMV008138 as IspD the third enzyme of the MEP pathway.References1) Yao Zhong-Ke Krai Priscilla M. et al. “Determination of the active stereoisomer of the MEP pathway-targeting antimalarial agent MMV008138 and initial structure-activity studies.” Bioorganic & Medicinal Chemistry Letter 2015 25 1515-15192) Wu W. Herrera Z Ebert D. Baska K.; Cho S.H.; Derisi J. I.; Yeh E

FR900098 an analog of the naturally occurring antibiotic Fosmidomycin inhibits 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) an enzyme in the non-mevanolate pathway for isoprenoid biosynthesis. The non-mevanolate or MEP pathway is essential in gram-negative some gram-positive bacteria plants and protozoa making it an attractive pathway to target for antibiotics since mammals use the mevalonate pathway to synthesize isoprenoids. FR900098 is twice as effective as Fosmidomycin against P. faliciparum in vitro.References Powered by Bioz See more details on Bioz1) E. Iguchi et al. “Studies on new phosphonic acid antibiotics. II. Taxonomic studies on producing organisms of the phosphonic acid and related compounds” The Journal of Antibiotics 33 1980 19–23.2) H. Jomaa et al. “Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs.” Science 285 1999 1573-1576.3) T. Umeda et al. “Molecular Basis of Fosmidomycin’s action on

 The Collagen Hybridizing Peptides are products of 3-Helix Inc.The collagen hybridizing peptide (CHP) is a novel and unique peptide that specifically binds unfolded collagen chains both in vitro and in vivo [1 2 3]. By sharing the Gly-X-Y repeating sequence of natural collagen CHP has a strong capability to hybridize with denatured collagen chains by reforming the triple helical structure in a fashion similar to DNA fragments annealing to complementary DNA strands. CHP is extremely specific: it has negligible affinity to intact collagen molecules due to lack of binding sites and it is inert towards non-specific binding because of its neutral and hydrophilic nature.CHP is a powerful histopathology tool which enables straightforward detection of inflammation and tissue damage caused by a large variety of diseases as well as tissue remodeling during development and aging [3]. CHP robustly visualizes the pericellular matrix turnover caused by proteolytic migration of cancer cells