Summary: 6-carbon straight-chain or branched ketones.

Top Publications

  1. Zhukovskaya N, Fukuzawa M, Yamada Y, Araki T, Williams J. The Dictyostelium bZIP transcription factor DimB regulates prestalk-specific gene expression. Development. 2006;133:439-48 pubmed
    ..Thus, DIF-1 regulates DimB activity to generate a gradient of ecmA expression in the prestalk zone of the slug. ..
  2. Serafimidis I, Kay R. New prestalk and prespore inducing signals in Dictyostelium. Dev Biol. 2005;282:432-41 pubmed
    ..All are distinct from currently identified factors. DIF-6, but not DIF-7 or PSI-2, appears to have an essential carbonyl group. Thus Dictyostelium may use extensive polyketide signaling in its development. ..
  3. Zhao W, Misumi J, Yasui T, Aoki K, Kimura T. Relationship between 2,5-hexanedione concentrations in nerve, serum, and urine alone or under co-treatment with different doses of methyl ethyl ketone, acetone, and toluene. Neurochem Res. 1998;23:837-43 pubmed
    ..6 mmol/kg co-treated solvent. These results show that SC can be used in estimating NC in the 2,5-HD alone or co-treated groups, and UC can be used in estimating SC in the 2,5-HD alone group. ..
  4. Kubohara Y, Hosaka K. The putative morphogen, DIF-1, of Dictyostelium discoideum activates Akt/PKB in human leukemia K562 cells. Biochem Biophys Res Commun. 1999;263:790-6 pubmed
    ..These results indicate that DIF-1 activates Akt/PKB possibly via cytosolic calcium and subsequent activation of PI3-kinase and also that PMA activates Akt/PKB in a PI3-kinase-independent manner. ..
  5. Kay R, Thompson C. Cross-induction of cell types in Dictyostelium: evidence that DIF-1 is made by prespore cells. Development. 2001;128:4959-66 pubmed
    ..We propose that prespore cells cross-induce the differentiation of prestalk-O cells by making DIF-1, and that this is one of the regulatory loops that sets the proportion of prespore-to-prestalk cells in the aggregate. ..
  6. Takahashi Yanaga F, Taba Y, Miwa Y, Kubohara Y, Watanabe Y, Hirata M, et al. Dictyostelium differentiation-inducing factor-3 activates glycogen synthase kinase-3beta and degrades cyclin D1 in mammalian cells. J Biol Chem. 2003;278:9663-70 pubmed
    ..These results suggested that DIF-3 activates GSK-3beta to accelerate the proteolysis of cyclin D1 and that this mechanism is involved in the DIF-3-induced G(0)/G(1) arrest in mammalian cells. ..
  7. Moffit J, Bryant B, Hall S, Boekelheide K. Dose-dependent effects of sertoli cell toxicants 2,5-hexanedione, carbendazim, and mono-(2-ethylhexyl) phthalate in adult rat testis. Toxicol Pathol. 2007;35:719-27 pubmed
    ..In addition, this work is fundamental to a planned investigation of the histopathologic and gene expression changes associated with testicular toxicant co-exposures, which may occur both occupationally and environmentally. ..
  8. Neumann C, Walsh C, Kay R. A flavin-dependent halogenase catalyzes the chlorination step in the biosynthesis of Dictyostelium differentiation-inducing factor 1. Proc Natl Acad Sci U S A. 2010;107:5798-803 pubmed publisher
  9. Maruo T, Sakamoto H, Iranfar N, Fuller D, Morio T, Urushihara H, et al. Control of cell type proportioning in Dictyostelium discoideum by differentiation-inducing factor as determined by in situ hybridization. Eukaryot Cell. 2004;3:1241-8 pubmed
    ..Removal of prespore cells resulted in cell type conversion in both wild-type and DIF-less anterior fragments. Thus, DIF-1 appears to act in concert with other processes to establish cell type proportions. ..

More Information


  1. Shimizu K, Murata T, Tagawa T, Takahashi K, Ishikawa R, Abe Y, et al. Calmodulin-dependent cyclic nucleotide phosphodiesterase (PDE1) is a pharmacological target of differentiation-inducing factor-1, an antitumor agent isolated from Dictyostelium. Cancer Res. 2004;64:2568-71 pubmed
  2. Mateus M, dos Santos A, Batoréu M. Evidence of zinc protection against 2,5-hexanedione neurotoxicity: correlation of neurobehavioral testing with biomarkers of excretion. Neurotoxicology. 2002;23:747-54 pubmed
    ..Moreover, pyrrole derivatives are good predictive biochemical biomarkers of 2,5-HD exposure and could be used as a complementary tool to characterize its neurotoxic effects. ..
  3. DeCaprio A, Kinney E, LoPachin R. Comparative covalent protein binding of 2,5-hexanedione and 3-acetyl-2,5-hexanedione in the rat. J Toxicol Environ Health A. 2009;72:861-9 pubmed publisher
    ..Based on these data, further studies are required to fully assess the neurotoxic potency of AcHD and other non-cross-linking analogues as compared to HD. ..
  4. Huang E, Blagg S, Keller T, Katoh M, Shaulsky G, Thompson C. bZIP transcription factor interactions regulate DIF responses in Dictyostelium. Development. 2006;133:449-58 pubmed
    ..DimA and DimB are therefore direct regulators of cellular responses to DIF-1. ..
  5. Williams J. Transcriptional regulation of Dictyostelium pattern formation. EMBO Rep. 2006;7:694-8 pubmed
  6. Yamasaki H, Sandrof M, Boekelheide K. Suppression of radiation-induced testicular germ cell apoptosis by 2,5-hexanedione pretreatment. I. Histopathological analysis reveals stage dependence of attenuated apoptosis. Toxicol Sci. 2010;117:449-56 pubmed publisher
  7. Kikuchi H, Oshima Y, Ichimura A, Gokan N, Hasegawa A, Hosaka K, et al. Anti-leukemic activities of Dictyostelium secondary metabolites: a novel aromatic metabolite, 4-methyl-5-n-pentylbenzene-1,3-diol, isolated from Dictyostelium mucoroides suppresses cell growth in human leukemia K562 and HL-60 cells. Life Sci. 2006;80:160-5 pubmed
    ..discoideum. The present results indicate that MPBD, DGs or their derivatives may have therapeutic potential in the treatment of cancer and confirm our expectations regarding cellular slime molds as drug resources. ..
  8. Boekelheide K, Fleming S, Allio T, Embree Ku M, Hall S, Johnson K, et al. 2,5-hexanedione-induced testicular injury. Annu Rev Pharmacol Toxicol. 2003;43:125-47 pubmed
    ..The goal is to evaluate the technical and conceptual approaches used to assess 2,5-HD-induced testicular injury, to highlight unanswered questions, and to identify fruitful avenues of future research. ..
  9. Keller T, Thompson C. Cell type specificity of a diffusible inducer is determined by a GATA family transcription factor. Development. 2008;135:1635-45 pubmed publisher
    ..They also reveal that a non-positional signal can regulate the differentiation of multiple cell types through differential interpretation in receiving cells. ..
  10. Kubohara Y. Effects of differentiation-inducing factors of Dictyostelium discoideum on human leukemia K562 cells: DIF-3 is the most potent anti-leukemic agent. Eur J Pharmacol. 1999;381:57-62 pubmed
    ..The present results suggest new routes for the development of more potent and effective anti-tumor agents. ..
  11. Matsuda T, Takahashi Yanaga F, Yoshihara T, Maenaka K, Watanabe Y, Miwa Y, et al. Dictyostelium differentiation-inducing factor-1 binds to mitochondrial malate dehydrogenase and inhibits its activity. J Pharmacol Sci. 2010;112:320-6 pubmed
    ..These results suggest that the inhibition of mMDH activity by DIF-1 and 2-MIDIF-1 could be one of the mechanisms to induce anti-proliferative effects, independent of the inhibition of the Wnt/beta-catenin signaling pathway. ..
  12. Song F, Yu S, Zhang C, Zhou G, Wang Q, Xie K. The reversibility of neurofilaments decline induced by 2,5-hexanedione in rat nerve tissues. Biochem Pharmacol. 2008;75:737-44 pubmed
    ..These findings suggest that HD-induced NFs decline is at least partially irreversible within the time frame of this study, which might be associated with the incomplete recovery of neurological dysfunctions of HD-treated rats. ..
  13. Austin M, Saito T, Bowman M, Haydock S, Kato A, Moore B, et al. Biosynthesis of Dictyostelium discoideum differentiation-inducing factor by a hybrid type I fatty acid-type III polyketide synthase. Nat Chem Biol. 2006;2:494-502 pubmed
    ..The crystal structure of a steely C-terminal domain confirms conservation of the homodimeric type III PKS fold. These findings suggest new bioengineering strategies for expanding the scope of fatty acid and polyketide biosynthesis. ..
  14. Saito T, Kato A, Kay R. DIF-1 induces the basal disc of the Dictyostelium fruiting body. Dev Biol. 2008;317:444-53 pubmed publisher
    ..Thus, DIF-1 is required for slug migration and specifies the anterior-like cells forming the basal disc and much of the lower cup; significantly the DIF-1 biosynthetic pathway may supply a second signal - dM-DIF-1. ..
  15. Kuwayama H, Kubohara Y. Differentiation-inducing factor-1 and -2 function also as modulators for Dictyostelium chemotaxis. PLoS ONE. 2009;4:e6658 pubmed publisher
    ..To our knowledge, this is the first report in any organism of physiologic modulators (small molecules) for chemotaxis having differentiation-inducing activity. ..
  16. Gokan N, Kikuchi H, Nakamura K, Oshima Y, Hosaka K, Kubohara Y. Structural requirements of Dictyostelium differentiation-inducing factors for their stalk-cell-inducing activity in Dictyostelium cells and anti-proliferative activity in K562 human leukemic cells. Biochem Pharmacol. 2005;70:676-85 pubmed
    ..The present findings would give us hints for identifying the target molecule(s) of DIFs and also for developing novel anti-cancer drugs. ..
  17. Nayler O, Insall R, Kay R. Differentiation-inducing-factor dechlorinase, a novel cytosolic dechlorinating enzyme from Dictyostelium discoideum. Eur J Biochem. 1992;208:531-6 pubmed
    ..It is essentially absent from growing cells and increases at the end of aggregation to reach a first peak of activity at the first finger stage, with a further rise at culmination. ..
  18. Lacey E, Ginzel M, Millar J, Hanks L. Male-produced aggregation pheromone of the cerambycid beetle Neoclytus acuminatus acuminatus. J Chem Ecol. 2004;30:1493-507 pubmed
    ..It is likely that males of other species in this large subfamily produce pheromones that are variations on this structural motif...
  19. Foster K, Shaulsky G, Strassmann J, Queller D, Thompson C. Pleiotropy as a mechanism to stabilize cooperation. Nature. 2004;431:693-6 pubmed
    ..discoideum because defecting on prestalk cell production results in an even greater reduction in spores. We propose that the evolution of pleiotropic links between cheating and personal costs can stabilize cooperative adaptations. ..
  20. Thompson C, Fu Q, Buhay C, Kay R, Shaulsky G. A bZIP/bRLZ transcription factor required for DIF signaling in Dictyostelium. Development. 2004;131:513-23 pubmed
    ..These results suggest that dimA encodes the key transcriptional regulator required to integrate DIF-1 signaling and subsequent patterning in Dictyostelium. ..
  21. Campion S, Houseman E, Sandrof M, Hensley J, Sui Y, Gaido K, et al. Suppression of radiation-induced testicular germ cell apoptosis by 2,5-hexanedione pretreatment. II. Gene array analysis reveals adaptive changes in cell cycle and cell death pathways. Toxicol Sci. 2010;117:457-65 pubmed publisher
  22. Mishra D, Pal R, Shaha C. Changes in cytosolic Ca2+ levels regulate Bcl-xS and Bcl-xL expression in spermatogenic cells during apoptotic death. J Biol Chem. 2006;281:2133-43 pubmed
    ..Alternatively, Ca2+ ionophores caused an increase of Bcl-xS encoding isoform over the Bcl-xL-encoding isoform. Therefore, this study proposes a role for Ca2+ in regulation of Bcl-xS and Bcl-xL expression and ultimately cell fate. ..
  23. Kay R. The biosynthesis of differentiation-inducing factor, a chlorinated signal molecule regulating Dictyostelium development. J Biol Chem. 1998;273:2669-75 pubmed
    ..It is proposed that DIF-1 is made by the initial assembly of a C12 polyketide skeleton, which is then chlorinated and methylated. ..
  24. Fukuzawa M, Zhukovskaya N, Yamada Y, Araki T, Williams J. Regulation of Dictyostelium prestalk-specific gene expression by a SHAQKY family MYB transcription factor. Development. 2006;133:1715-24 pubmed
    ..The ecmA gene is not induced by DIF-1 in a mybE-strain. Thus, MybE is necessary for DIF-1 responsiveness and for the correct differentiation of pstO cells and ALCs. ..
  25. Bryant B, Yamasaki H, Sandrof M, Boekelheide K. Spermatid head retention as a marker of 2,5-hexanedione-induced testicular toxicity in the rat. Toxicol Pathol. 2008;36:552-9 pubmed publisher
    ..There was no evidence of other histopathological alterations. These data identify RSH as a sensitive histopathological marker of testicular toxicity for subacute HD exposure. ..
  26. Manini P, Andreoli R, Mutti A, Bergamaschi E, Franchini I. Determination of free and glucuronated hexane metabolites without prior hydrolysis by liquid- and gas-chromatography coupled with mass spectrometry. Toxicol Lett. 1999;108:225-31 pubmed
    ..Free' 2,5-HD seems to be both suitable from an analytical point of view and meaningful for biological monitoring purposes, provided that conjugate metabolites are rapidly removed from the body leading to a negligible neurotoxic risk. ..
  27. Araki T, Langenick J, Gamper M, Firtel R, Williams J. Evidence that DIF-1 and hyper-osmotic stress activate a Dictyostelium STAT by inhibiting a specific protein tyrosine phosphatase. Development. 2008;135:1347-53 pubmed publisher
  28. Takahashi Yanaga F, Mori J, Matsuzaki E, Watanabe Y, Hirata M, Miwa Y, et al. Involvement of GSK-3beta and DYRK1B in differentiation-inducing factor-3-induced phosphorylation of cyclin D1 in HeLa cells. J Biol Chem. 2006;281:38489-97 pubmed
    ..These results suggest that DIF-3 induces degradation of cyclin D1 through the GSK-3beta- and DYRK1B-mediated threonine phosphorylation in HeLa cells. ..
  29. Kanai M, Konda Y, Nakajima T, Izumi Y, Kanda N, Nanakin A, et al. Differentiation-inducing factor-1 (DIF-1) inhibits STAT3 activity involved in gastric cancer cell proliferation via MEK-ERK-dependent pathway. Oncogene. 2003;22:548-54 pubmed
  30. Maeda M, Sakamoto H, Iranfar N, Fuller D, Maruo T, Ogihara S, et al. Changing patterns of gene expression in dictyostelium prestalk cell subtypes recognized by in situ hybridization with genes from microarray analyses. Eukaryot Cell. 2003;2:627-37 pubmed
    ..These results indicate that differentiation of some aspects of PstO cells can occur in the absence of DIF-1. ..
  31. Mori J, Takahashi Yanaga F, Miwa Y, Watanabe Y, Hirata M, Morimoto S, et al. Differentiation-inducing factor-1 induces cyclin D1 degradation through the phosphorylation of Thr286 in squamous cell carcinoma. Exp Cell Res. 2005;310:426-33 pubmed
    ..These results suggest that DIF-1 induces degradation of cyclin D1 through the GSK-3beta-mediated phosphorylation of Thr286. ..
  32. Thompson C, Kay R. The role of DIF-1 signaling in Dictyostelium development. Mol Cell. 2000;6:1509-14 pubmed
    ..We conclude that pstO and pstA cells are in fact induced by separate signals and that DIF-1 is the pstO inducer. Positional information, in the form of DIF-1 gradients, is evidently not required for pstO cell induction. ..
  33. Hanks L, Millar J, Moreira J, Barbour J, Lacey E, McElfresh J, et al. Using generic pheromone lures to expedite identification of aggregation pheromones for the cerambycid beetles Xylotrechus nauticus, Phymatodes lecontei, and Neoclytus modestus modestus. J Chem Ecol. 2007;33:889-907 pubmed
    ..Overall, the attraction of multiple species from different cerambycine tribes to this compound at a single field site supports the hypothesis that the hydroxyketone pheromone structural motif is highly conserved within this subfamily. ..
  34. Akaishi E, Narita T, Kawai S, Miwa Y, Sasaguri T, Hosaka K, et al. Differentiation-inducing factor-1-induced growth arrest of K562 leukemia cells involves the reduction of ERK1/2 activity. Eur J Pharmacol. 2004;485:21-9 pubmed
    ..The present results suggest that ERK inactivation may be involved in DIF-1-induced growth arrest and that PI-3K activity is not required for DIF-1-induced growth arrest in K562 cells. ..
  35. Matsuzaki E, Takahashi Yanaga F, Miwa Y, Hirata M, Watanabe Y, Sato N, et al. Differentiation-inducing factor-1 alters canonical Wnt signaling and suppresses alkaline phosphatase expression in osteoblast-like cell lines. J Bone Miner Res. 2006;21:1307-16 pubmed
    ..To our knowledge, this is the first report to analyze the role of the TCF/LEF binding site (-1023/-1017 bp) of the ALP gene promoter in osteoblast-like cell lines. ..
  36. Motohashi K, Morita N, Kato A, Saito T. Identification of des-methyl-DIF-1 methyltransferase in Dictyostelium purpureum. Biosci Biotechnol Biochem. 2012;76:1672-6 pubmed
    ..This indicates that the stalk-inducing signal of DIF-1 and des-methyl-DIF-1 methyltransferase are conserved in D. purpureum. ..
  37. Yan J, Yin H, Liu Z, Chi D, Li Y, Fu Q, et al. [Effects of garlic oil, age and sex on n-hexane metabolism in rats]. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2011;29:49-52 pubmed
    ..6, 19.1 µg/ml, 19.1, 13.8 µg/ml each (different non-significantly). GO reduces production of 2, 5-hexanedione in serum generated by n-hexane in rats; the metabolic capacity of low age rats on n-hexane is stronger than high age ones. ..
  38. Zhang C, Qi J, Cui D, Wang Q, Wang X. Platinum-catalyzed hydrative cyclization of 1,6-diynes for the synthesis of 3,5-substituted conjugated cyclohexenones. Molecules. 2010;15:5045-52 pubmed publisher
    ..We have developed a Pt(COD)Cl(2)-catalyzed hydrative cyclization of 1,6-diynes leading to the formation of functionalized cyclohexenones in good yields. ..
  39. Yamada Y, Kubohara Y, Kikuchi H, Oshima Y, Wang H, Ross S, et al. The Dictyostelium prestalk inducer DIF-1 directs phosphorylation of a bZIP transcription factor. Int J Dev Biol. 2013;57:375-81 pubmed publisher
    ..iii) We also present evidence that the kinase activity, which phosphorylates S590, is non-nuclear and that this signalling pathway is, in part at least, independent of the DIF-regulated STATc activation pathway. ..
  40. Moran J, Ehrhardt C, Wahl J, Kreuzer H, Wahl K. Integration of stable isotope and trace contaminant concentration for enhanced forensic acetone discrimination. Talanta. 2013;116:866-9 pubmed publisher
    ..The data presented here demonstrates the power of combining orthogonal data sets to enhance sample fingerprinting and highlights the role disparate data could play in future forensic investigations. ..
  41. Katzberg M, Wechler K, Muller M, Dünkelmann P, Stohrer J, Hummel W, et al. Biocatalytical production of (5S)-hydroxy-2-hexanone. Org Biomol Chem. 2009;7:304-14 pubmed publisher
    ..This study compares the whole-cell biocatalytic route with the enzymatic route to enantiopure (S)-2 and investigates factors determining performance and outcome of the bioreductions. ..
  42. Huchet G, Euerby M, MacKay S, Waigh R. The role of water in drug-receptor interactions. J Enzyme Inhib Med Chem. 2006;21:271-6 pubmed
    ..The results also suggest that water structure may impart sufficient energy to modify the conformational space of organic molecules through hydrogen bonding. ..
  43. Hamelin G, Charest Tardif G, Truchon G, Tardif R. Physiologically based modeling of n-hexane kinetics in humans following inhalation exposure at rest and under physical exertion: impact on free 2,5-hexanedione in urine and on n-hexane in alveolar air. J Occup Environ Hyg. 2005;2:86-97; quiz D6-7 pubmed
  44. LoPachin R, DeCaprio A. gamma-Diketone neuropathy: axon atrophy and the role of cytoskeletal protein adduction. Toxicol Appl Pharmacol. 2004;199:20-34 pubmed
    ..Evidence presented in this review suggests that "distal axonopathy" is an inaccurate classification and future nosological schemes should be based on the apparent primacy of axon atrophy. ..
  45. Hamelin G, Truchon G, Tardif R. Comparison of unchanged n-hexane in alveolar air and 2,5-hexanedione in urine for the biological monitoring of n-hexane exposure in human volunteers. Int Arch Occup Environ Health. 2004;77:264-70 pubmed
  46. Song F, Wang Q, Zeng T, Yu L, Zhu Z, Xie K. [Dynamic study of neurofilament contents in rat's spinal cord induced by 2, 5-hexanedione]. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2008;26:588-91 pubmed
    ..8912, 0.9282 and 0.8981 (P < 0.01) respectively. The declines of NFs are high-ly related to neurobehavioral abnormality of 2, 5-HD-treated animals, and involved in the development of n-hexane neuropathy. ..
  47. Mikolajek R, Spiess A, Pohl M, Buchs J. Propioin synthesis using thiamine diphosphate-dependent enzymes. Biotechnol Prog. 2009;25:132-8 pubmed publisher
    ..Both enzymes produce propioin with opposite enantiomeric excess: BAL produced the (S)-propioin (ee of 35%), whereas BFD yielded the (R)-enantiomer (ee of 67%). ..
  48. Qian Y, Zeng F. Re-establishment of spermatogenesis by diethylstilbestrol after 2,5-hexanedione-induced irreversible testicular atrophy in rats. J Huazhong Univ Sci Technolog Med Sci. 2008;28:179-81 pubmed publisher
    ..Estrogen plays an important part in spermatogenesis, and the role of estrogen in spermatogenesis is more than suppressing the hypothalamo-pituitary-testis axis. ..
  49. Scott J, Dorr R, Samulitis B, Landowski T. Imexon-based combination chemotherapy in A375 human melanoma and RPMI 8226 human myeloma cell lines. Cancer Chemother Pharmacol. 2007;59:749-57 pubmed
    ..These results suggest that combinations of imexon with alkylating agents and pyrimidine-based antimetabolites are rational to pursue in therapeutic studies in vivo. ..
  50. den Brok M, Nuijen B, Lutz C, Opitz H, Beijnen J. Pharmaceutical development of a lyophilised dosage form for the investigational anticancer agent Imexon using dimethyl sulfoxide as solubilising and stabilising agent. J Pharm Sci. 2005;94:1101-14 pubmed
    ..Imexon 100 mg/vial lyophilised product was shown stable for at least 12 months of storage at -20 degrees C and +5 +/- 3 degrees C in the dark. ..
  51. Ito S, Umehara M, Hanada A, Kitahata N, Hayase H, Yamaguchi S, et al. Effects of triazole derivatives on strigolactone levels and growth retardation in rice. PLoS ONE. 2011;6:e21723 pubmed publisher
    ..These results suggest that TIS108 has a potential to be applied in the control of root parasitic weeds germination. ..
  52. Schmuck G, Schluter G. An in vitro model for toxicological investigations of environmental neurotoxins in primary neuronal cell cultures. Toxicol Ind Health. 1996;12:683-96 pubmed
    ..Therefore, the determination of cell-specific end points is necessary to detect the neurotoxic potency and quality of a compound, whereas the cytotoxicity assay limited the tested concentration range. ..
  53. Abou Donia M, Lapadula D, Suwita E. Cytoskeletal proteins as targets for organophosphorus compound and aliphatic hexacarbon-induced neurotoxicity. Toxicology. 1988;49:469-77 pubmed
    ..This treatment also decreased protein phosphorylation of neurofilament proteins as well as MAP-2. These studies demonstrate the involvement of cytoskeletal proteins in the molecular pathogenesis of chemical-induced neurotoxicity. ..