Details of a Researcher - Kikuchi, Haruhisa

Papers - Kikuchi, Haruhisa

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Two New Terpenes Isolated from Dictyostelium Cellular Slime Molds

Hitomi Sasaki, Yuzuru Kubohara, Hirotaka Ishigaki, Katsunori Takahashi, Hiromi Eguchi, Akihiro Sugawara, Yoshiteru Oshima, Haruhisa Kikuchi

Molecules (MDPI AG) 25 ( 12 ) 2895 - 2895 2020.06

Research paper (scientific journal), Joint Work, Accepted

We report a protoilludane-type sesquiterpene, mucoroidiol, and a geranylated bicyclogermacranol, firmibasiol, isolated from Dictyostelium cellular slime molds. The methanol extracts of the fruiting bodies of cellular slime molds were separated by chromatographic methods to give these compounds. Their structures have been established by several spectral means. Mucoroidiol and firmibasiol are the first examples of more modified and oxidized terpenoids isolated from cellular slime molds. Mucoroidiol showed moderate osteoclast-differentiation inhibitory activity despite demonstrating very weak cell-proliferation inhibitory activity. Therefore, cellular slime molds produce considerably diverse secondary metabolites, and they are promising sources of new natural product chemistry.

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Downregulation of PD‑L1 via amide analogues of brefelamide: Alternatives to antibody‑based cancer immunotherapy

Jing Zhang, Osamu Yamada, Shinya Kida, Shinya Murase, Toshio Hattori, Yoshiteru Oshima, Haruhisa Kikuchi

Experimental and Therapeutic Medicine (Spandidos Publications) 2020.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 1792-0981

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An automated microliter-scale high-throughput screening system (MSHTS) for real-time monitoring of protein aggregation using quantum-dot nanoprobes.

Rina Sasaki, Reina Tainaka, Yuichi Ando, Yurika Hashi, Hadya V Deepak, Yoshiko Suga, Yuta Murai, Masaki Anetai, Kenji Monde, Kiminori Ohta, Ikuko Ito, Haruhisa Kikuchi, Yoshiteru Oshima, Yasuyuki Endo, Hitomi Nakao, Masafumi Sakono, Koji Uwai, Kiyotaka Tokuraku

Scientific reports (Scientific Reports) 9 ( 1 ) 2587 - 2587 2019.12

Research paper (scientific journal), Joint Work, Accepted

Protein aggregation is the principal component of numerous protein misfolding pathologies termed proteinopathies, such as Alzheimer's disease, Parkinson's disease, prion disease, and AA amyloidosis with unmet treatment needs. Protein aggregation inhibitors have great potential for the prevention and treatment of proteinopathies. Here we report the development of an automated real-time microliter-scale high throughput screening (MSHTS) system for amyloid aggregation inhibitors using quantum-dot nanoprobes. Screening 504 crude extracts and 134 low molecular weight aromatic compounds revealed the relationship of amyloid-β (Aβ) aggregation inhibitory activities of plant extracts using a plant-based classification. Within the eudicots, rosids, Geraniales and Myrtales showed higher activity. Screening low molecular weight aromatic compounds demonstrated that the structure of tropolone endows it with potential Aβ aggregation inhibitory activity. The activity of the most active tropolone derivative was higher than that of rosmarinic acid. MSHTS also identified three chaperone molecules as tau aggregation inhibitors. These results demonstrate that our automated MSHTS system is a novel and robust tool that can be adapted to a wide range of compounds and aggregation-prone polypeptides.

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Structure and biological activity of metarhizin C, a stereoisomer of BR-050 from Tolypocladium album RK17-F0007.

Nogawa, T, Kawatani, M, Okano, A, Futamura, Y, Aono, H, Shimizu, T, Kato, N, Kikuchi, H, Osada, H

The Journal of Antibiotics (Journal of Antibiotics) 72 ( 12 ) 996 - 1000 2019.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 00218820

Metarhizin C, a stereoisomer of BR-050 was isolated from a fungus Tolypocladium album RK17-F0007 through a screening program to search for new antitumor compounds. A structure of the isomer was determined by spectroscopic methods including detailed analysis of NOESY correlation and mass spectrometry, and found to be identical to that of 3-desacylmetarhizin A with the absolute structure. Previously, it had been isolated by Kikuchi et al and proposed as BR-050 including the stereo-structure. However, detailed analysis for the newly isolated isomer confirmed that 3-desacylmetarhizin A was not identical to BR-050. Therefore, we assigned it metarhizin C as a new BR-050 isomer. Metarhizin C showed selective cytotoxicity against osteosarcoma MG-63 cells in a glucose independent condition with IC50 value of 0.79 µg/ml, while > 30 µg/ml of IC50 value in a normal condition, and inhibited a mitochondrial respiration.

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Differentiation-inducing factor-1 prevents hepatic stellate cell activation through inhibiting GSK3β inactivation.

Furukawa, S, Yamaguchi, M, Ooka, A, Kikuchi, H, Ishikawa, T, Saito, S

Biochemical and Biophysical Research Communications (Elsevier BV) 520 ( 1 ) 140 - 144 2019.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 0006291X

Differentiation-inducing factor-1 (DIF-1), a morphogen produced by the cellular slime mold Dictyostelium discoideum, is a natural product that has attracted considerable attention for its antitumor properties. Here, we report a novel inhibitory effect of DIF-1 on the activation of hepatic stellate cells (HSCs) responsible for liver fibrosis. DIF-1 drastically inhibited transdifferentiation of quiescent HSCs into myofibroblastic activated HSCs in a concentration-dependent manner, thus conferring an antifibrotic effect against in the liver. Neither SQ22536, an adenylate cyclase inhibitor, nor ODQ, a guanylate cyclase inhibitor, showed any effect on the inhibition of HSC activation by DIF-1. In contrast, TWS119, a glycogen synthase kinase 3β (GSK3β) inhibitor, attenuated the inhibitory effect of DIF-1. Moreover, the level of inactive GSK3β (phosphorylated at Ser9) was significantly reduced by DIF-1. DIF-1 also inhibited nuclear translocation of β-catenin and reduced the level of non-phospho (active) β-catenin. These results suggest that DIF-1 inhibits HSC activation by disrupting the Wnt/β-catenin signaling pathway through dephosphorylation of GSK3β. We propose that DIF-1 is a possible candidate as a therapeutic agent for preventing liver fibrosis.

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Conformational heterogeneity in apo and drug-bound structures of Toxoplasma gondii proryl tRNA synthase.

Mishra S, Malhotra, N, Kumari, S, Sato M, Kikuchi, H, Yogavel M, Sharma A

Acta Crystallographica Section F (Acta Crystallographica Section F: Structural Biology Communications) 75 714 - 724 2019.11

Research paper (scientific journal), Joint Work, Accepted

Prolyl-tRNA synthetase (PRS) is a member of the aminoacyl-tRNA synthetase family that drives protein translation in cells. The apicomplexan PRSs are validated targets of febrifugine (FF) and its halogenated derivative halofuginone (HF). PRSs are of great interest for drug development against Plasmodium falciparum and Toxoplasma gondii. In this study, structures of apo and FF-bound T. gondii (TgPRS) are revealed and the dynamic nature of the conformational changes that occur upon FF binding is unraveled. In addition, this study highlights significant conformational plasticity within two different crystal structures of apo PRSs but not within drug-bound PRSs. The apo PRSs exist in multi-conformational states and manifest pseudo-dimeric structures. In contrast, when FF is bound the PRS dimer adopts a highly symmetrical architecture. It is shown that TgPRS does not display extant fold switching, in contrast to P. falciparum PRS, despite having over 65% sequence identity. Finally, structure-comparison analyses suggest the utility of r.m.s.d. per residue (r.m.s.d./res) as a robust tool to detect structural alterations even when the r.m.s.d. is low. Apo TgPRS reveals FF/HF-induced rigidity and this work has implications for drug-design studies that rely on the apo structures of target proteins.

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Inhibition of inflammatory-molecule synthesis in THP-1 cells stimulated with phorbol 12-myristate 13-acetate by brefelamide derivatives

Gaowa Bai, Takashi Matsuba, Haruhisa Kikuchi, Haorile Chagan-Yasutan, Hirotoshi Motoda, Ryo Ozuru, Osamu Yamada, Yoshiteru Oshima, Toshio Hattori

International Immunopharmacology (Elsevier BV) 75 105831 - 105831 2019.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 15675769

Plasma osteopontin (OPN) levels are elevated in tuberculosis patients and may involve granuloma formation. New inhibitors using brefelamide, an aromatic amide isolated from Dictyostelium cellular slime molds that may inhibit OPN transcription in A549 cells at 1 μM concentration, were synthesized as compounds C, D, and E. Their inhibitory activity against OPN synthesis in phorbol 12-myristate 13-acetate (PMA)-stimulated THP-1 cells was confirmed using enzyme-linked immunosorbent assay (ELISA), a multicolor immune-fluorescent microscope, and western blot. In the ELISA performed using full-length OPN, each compound showed significant inhibition in culture supernatants with half maximal inhibitory concentration (IC50) values of 1.6, 1.8, and 2.2 μM for C, D, and E, respectively. In another ELISA to detect the immune-related form of OPN, IC50 values were 0.6, 1.2, and 2.5 μM for compounds C, D, and E, respectively. The decreases in OPN expression and synthesis were confirmed using immunofluorescence and western blot studies using compound-treated cells or cell lysates. Luminex assay of the supernatants of PMA-treated THP-1 cells showed significant reduction in the synthesis of interleukin (IL)-1β, galectin-9, and tumor necrosis factor (TNF)-α. Elucidation of the detailed mechanisms of the biological activities of these compounds would be necessary; however, they may be used in clinical trials for infectious diseases, inflammatory disorders, and cancer.

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Identification of Celastramycin as a Novel Therapeutic Agent for Pulmonary Arterial Hypertension.

Ryo Kurosawa, Kimio Satoh, Nobuhiro Kikuchi, Haruhisa Kikuchi, Daisuke Saigusa, Md Elias Al-Mamun, Mohammad A H Siddique, Junichi Omura, Taijyu Satoh, Shinichiro Sunamura, Masamichi Nogi, Kazuhiko Numano, Satoshi Miyata, Akira Uruno, Kuniyuki Kano, Yotaro Matsumoto, Takayuki Doi, Junken Aoki, Yoshiteru Oshima, Masayuki Yamamoto, Hiroaki Shimokawa

Circulation research (Circulation Research) 125 ( 3 ) 309 - 327 2019.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 00097330

RATIONALE: Pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs) accompanying increased production of inflammatory factors and adaptation of the mitochondrial metabolism to a hyperproliferative state. However, all the drugs in clinical use target pulmonary vascular dilatation, which may not be effective for patients with advanced PAH. OBJECTIVE: We aimed to discover a novel drug for PAH that inhibits PASMC proliferation. METHODS AND RESULTS: We screened 5562 compounds from original library using high-throughput screening system to discover compounds which inhibit proliferation of PASMCs from patients with PAH (PAH-PASMCs). We found that celastramycin, a benzoyl pyrrole-type compound originally found in a bacteria extract, inhibited the proliferation of PAH-PASMCs in a dose-dependent manner with relatively small effects on PASMCs from healthy donors. Then, we made 25 analogs of celastramycin and selected the lead compound, which significantly inhibited cell proliferation of PAH-PASMCs and reduced cytosolic reactive oxygen species levels. Mechanistic analysis demonstrated that celastramycin reduced the protein levels of HIF-1α (hypoxia-inducible factor 1α), which impairs aerobic metabolism, and κB (nuclear factor-κB), which induces proinflammatory signals, in PAH-PASMCs, leading to reduced secretion of inflammatory cytokine. Importantly, celastramycin treatment reduced reactive oxygen species levels in PAH-PASMCs with increased protein levels of Nrf2 (nuclear factor erythroid 2-related factor 2), a master regulator of cellular response against oxidative stress. Furthermore, celastramycin treatment improved mitochondrial energy metabolism with recovered mitochondrial network formation in PAH-PASMCs. Moreover, these celastramycin-mediated effects were regulated by ZFC3H1 (zinc finger C3H1 domain-containing protein), a binding partner of celastramycin. Finally, celastramycin treatment ameliorated pulmonary hypertension in 3 experimental animal models, accompanied by reduced inflammatory changes in the lungs. CONCLUSIONS: These results indicate that celastramycin ameliorates pulmonary hypertension, reducing excessive proliferation of PAH-PASMCs with less inflammation and reactive oxygen species levels, and recovered mitochondrial energy metabolism. Thus, celastramycin is a novel drug for PAH that targets antiproliferative effects on PAH-PASMCs.

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Halogen-substituted derivatives of Dictyostelium differentiation-inducing factor-1 suppress serum-induced cell migration of human breast cancer MDA-MB-231 cells in vitro.

Totsuka, K, Makioka, Y, Iizumi, K, Takahashi, K, Oshima, Y, Kikuchi, H, Kubohara, Y

Biomolecules (Biomolecules) 9 ( 7 ) 256 2019.07

Research paper (scientific journal), Joint Work, Accepted

Triple-negative breast cancer (TNBC) is highly proliferative and metastatic, and because it lacks three major molecular targets for chemotherapy (estrogen receptor, progesterone receptor, and human epidermal receptor 2), it is extremely refractory. Differentiation-inducing factor 1 (DIF-1) and DIF-3, which are chlorinated alkylphenones, are lead anticancer compounds found in the cellular slime mold Dictyostelium discoideum. Here, we examined the in vitro effects of DIF-1, DIF-3, and 25 DIF derivatives on cell proliferation and serum-induced cell migration in human MDA-MB-231 cells, a model TNBC cell line. We found that Br-DIF-1, a chlorine-to-bromine-substituted derivative of DIF-1, strongly suppressed cell migration (IC50, 3.8 µM) with negligible effects on cell proliferation (IC50, >20 µM). We then synthesized 18 derivatives of Br-DIF-1 and examined the in vitro effects of these derivatives on cell proliferation and serum-induced cell migration in MDA-MB-231 cells. Among the derivatives, Br-DIF-1(+1), Br-DIF-1(+2), and Br-DIF-3(+2) exhibited strong anti-cell migration activities with IC50 values of 1.5, 1.0, and 3.1 µM, respectively, without affecting cell proliferation (IC50, >20 µM). These results suggest that these Br-DIF derivatives are good lead compounds for the development of anti-metastatic drugs against TNBC.

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Antimicrobial Activities of Dictyostelium Differentiation-Inducing Factors and Their Derivatives.

Kubohara, Y, Shiratsuchi Y, Ishigaki, H, Takahashi, K, Oshima, Y, Kikuchi, H

Biomolecules (Biomolecules) 9 ( 5 ) 163 2019.05

Research paper (scientific journal), Joint Work, Accepted

At the end of its life cycle, the cellular slime mold Dictyostelium discoideum forms a fruiting body consisting of spores and a multicellular stalk. Originally, the chlorinated alkylphenone differentiation-inducing factors (DIFs) -1 and -3 were isolated as stalk cell inducers in D. discoideum. Later, DIFs and their derivatives were shown to possess several biologic activities including antitumor and anti-Trypanosoma properties. In this study, we examined the antibacterial activities of approximately 30 DIF derivatives by using several bacterial species. Several of the DIF derivatives strongly suppressed the growth of the Gram-positive bacteria Staphylococcus aureus, Bacillus subtilis, and Enterococcus faecalis and Enterococcus faecium, at minimum inhibitory concentrations (MICs) in the sub-micromolar to low-micromolar range. In contrast, none of the DIF derivatives evaluated had any noteworthy effect on the growth of the Gram-negative bacterium Escherichia coli (MIC, >100 µM). Most importantly, several of the DIF derivatives strongly inhibited the growth of methicillin-resistant S. aureus and vancomycin-resistant E. faecalis and E. faecium. Transmission electron microscopy revealed that treatment with DIF derivatives led to the formation of distinct multilayered structures consisting of cell wall or plasma membrane in S. aureus. The present results suggest that DIF derivatives are good lead compounds for developing novel antimicrobials.

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Prenylated quinolinecarboxylic acid derivative prevents neuronal cell death through inhibition of MKK4.

Ogura, M, Kikuchi, H, Shakespear N. B, Suzuki, T, Yamaki, J, Homma, M. K, Oshima, Y, Homma, Y

Biochemical Pharmacology (Biochemical Pharmacology) 162 109 - 122 2019.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 00062952

The development of neuroprotective agents is necessary for the treatment of neurodegenerative diseases. Here, we report PQA-11, a prenylated quinolinecarboxylic acid (PQA) derivative, as a potent neuroprotectant. PQA-11 inhibits glutamate-induced cell death and caspase-3 activation in hippocampal cultures, as well as inhibits N-Methyl-4-phenylpyridinium iodide- and amyloid β 1-42 -induced cell death in SH-SY5Y cells. PQA-11 also suppresses mitogen-activated protein kinase kinase 4 (MKK4) and c-jun N-terminal kinase (JNK) signaling activated by these neurotoxins. Quartz crystal microbalance analysis and in vitro kinase assay reveal that PQA-11 interacts with MKK4, and inhibits its sphingosine-induced activation. The administration of PQA-11 by intraperitoneal injection alleviates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced degeneration of nigrostriatal dopaminergic neurons in mice. These results suggest that PQA-11 is a unique MKK4 inhibitor with potent neuroprotective effects in vitro and in vivo. PQA-11 may be a valuable lead for the development of novel neuroprotectants.

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Construction of a Meroterpenoid-like Compounds Library Based on Diversity-Enhanced Extracts.

Kikuchi, H, Kawai, K, Nakashiro, Y, Yonezawa, T, Kawaji, K, Kodama, E. N, Oshima, Y

Chemistry - A European Journal (Chemistry - A European Journal) 25 ( 4 ) 1106 - 1112 2019.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 09476539

The structural diversity of natural products and their derivatives have long contributed to the development of new drugs. However, the difficulty in obtaining compounds bearing skeletally novel structures has recently led to a decline of pharmaceutical research into natural products. This paper reports the construction of a meroterpenoid-like library containing 25 compounds with diverse molecular scaffolds obtained from diversity-enhanced extracts. This method constitutes an approach for increasing the chemical diversity of natural-product-like compounds by combining natural product chemistry and diversity-oriented synthesis. Extensive pharmacological screening of the library revealed promising compounds for anti-osteoporotic and anti-lymphoma/leukemia drugs. This result indicates that the use of diversity-enhanced extracts is an effective methodology for producing chemical libraries for the purpose of drug discovery.

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H-1. Mg, K-containing microparticle: A possible active principle of EM fermentation product

Higashinakagawa T., Kiku-Chi H., Kuwayama H.

Biopolymers and Cell (Biopolymers and Cell) 35 ( 3 ) 2019

ISSN 02337657

EM represents Effective Microorganisms, a microbial consortium consisting mainly of photosynthetic bacteria, lactic acid bacteria and yeast. Various effects on cells of EM fermentation product were reported in the previous WBW25 Meeting in 2017. Here, we report our attempt to identify its active principle and the ongoing preliminary results. The activity was assayed by promoted formation of fruiting body of Dictyostelium discoideum. The EM fermentation product was first subjected to liquid-liquid separation, with the activity being recovered in aqueous phase. Concentrated aqueous fraction was further subjected to column chromatography. No activity was detected in any eluant, while almost all activity was recovered in residual insoluble material. The application of conventional organic chemistry procedures did not lead to any informative results. Acid treatment of the insoluble material produced air bubbles, suggesting it to be composed of some inorganic carbonate. Viewed under scanning electronmicroscope, these residues revealed spherical particles of μm range. Energy Dispersive X-ray (EDX) Spectroscopy pointed to the existence of magnesium and, to a certain extent, potassium. In a separate experiment, acid treatment and alkali neutralization of EM fermentation product completely wiped out the stimulatory activity of fruiting body formation. These lines of evidence indicate these Mg, K-containing microparticle to be active principle of EM fermentation product, at least, in regard to fruiting body formation in Dictyostelium discoideum. How these particles exert their effect is currently under extensive investigation.

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Dictyostelium: An Important Source of Structural and Functional Diversity in Drug Discovery (Review)

Kubohara, Y, Kikuchi, H

Cells 8 ( 1 ) 6 2019

Research paper (scientific journal), Joint Work, Accepted

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Removal of the E-olefin Barrier of Humulene Leading to Unnatural Terpenoid-like Skeletons.

Nishimura, T, Kawai, J, Oshima, Y, Kikuchi, H

Organic Letters (AMER CHEMICAL SOC) 20 ( 22 ) 7317 - 7320 2018.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 15237060

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合成化合物を対象とした新規免疫制御剤の探索

石垣宏尚, 高橋克典, 久保原禅, 菊地晴久, 藤田清貴

臨床化学 ((一社)日本臨床化学会) 47 ( Suppl.1 ) 312 - 312 2018.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 0370-5633

Developments toward the Production of Diverse Natural-Product-Like Compounds: Diversity-Oriented Synthesis and Diversity-Enhanced Extracts (Review)

Kikuchi H, Oshima Y

Heterocycles (Heterocycles) 96 ( 9 ) 1509 - 1527 2018

Research paper (scientific journal), Joint Work, Accepted, ISSN 03855414

Natural products and their derivatives have proven very useful in the search for biologically active compounds and in the development of new drugs because of their structural diversity. However, new approaches that may increase the chemical diversity of such natural products must be developed in order to retain the future usefulness of these compounds. Diversity-oriented synthesis (DOS) has recently emerged as an efficient methodology for constructing complex and diverse compounds from simple and similar precursors. Through the combination of natural product chemistry and DOS, we therefore propose a new approach, diversity-enhanced extracts, for increasing the diversity of natural-product-like compounds. This review describes recent developments toward the production of diverse natural-product-like compounds by DOS based on natural products and direct chemical derivatization of natural extracts, including diversity-enhanced extracts.

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Effect of brefelamide on proliferation of 1321N1 human astrocytoma cells induced by glial cell line-derived neurotrophic factor

S. Honma, K. Kouno, S. Takasaka, S. Mitazaki, S. Abe, H. Kikuchi, Y. Oshima, M. Yoshida

Pharmazie (Govi-Verlag Pharmazeutischer Verlag GmbH) 73 ( 1 ) 22 - 28 2018

Research paper (scientific journal), Joint Work, Accepted, ISSN 00317144

Malignant gliomas are highly resistant to chemotherapy and radiation and more effective options for treatment are urgently needed. We reported previously that the aromatic amide brefelamide, which is isolated from methanolic extracts of the cellular slime molds Dictyostelium giganteum and D. brefeldianum, hinders cellular proliferation in a glioma model utilizing 1321N1 human astrocytoma cells. Herein, we examined the mechanisms underlying the inhibition of 1321N1 cell proliferation by brefelamide. Glial cell line-derived neurotrophic factor (GDNF) was found to enhance the rate of proliferation of serum-free cultured 1321N1 cells, but did not affect proliferation in PC12 cells. Brefelamide pretreatment inhibited GDNF-induced cell proliferation and expression of rearranged during transfection (RET). GDNF enhanced the phosphorylation of extracellular signal-regulated kinase (ERK), AKT, and c-jun-N-terminal kinase (JNK)
however, brefelamide pretreatment inhibited these effects. Brefelamide also reduced the expression of GDNF mRNA and GDNF secretion. Together, the findings from this study indicate that brefelamide inhibits the proliferation of 1321N1 cell via several mechanisms including reduced GDNF receptor expression and GDNF secretion, and reduced phosphorylation of ERK, AKT, and JNK.

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Biological Activities of Novel Derivatives of Differentiation-Inducing Factor 3 from Dictyostelium discoideum

Katsunori Takahashi, Haruhisa Kikuchi, Van Hai Nguyen, Yoshiteru Oshima, Hirotaka Ishigaki, Junko Nakajima-Shimada, Yuzuru Kubohara

BIOLOGICAL & PHARMACEUTICAL BULLETIN (PHARMACEUTICAL SOC JAPAN) 40 ( 11 ) 1941 - 1947 2017.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 0918-6158

Differentiation-inducing factor-3 (DIF-3; 1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)hexan-1-one), which is found in the cellular slime mold Dictyostelium discoideum, is a potential candidate compound for the development of new medicines; DIF-3 and its derivatives possess several beneficial biological activities, including anti-tumor, anti-Trypanosoma cruzi, and immunoregulatory effects. To assess the relationship between the biological activities of DIF-3 and its chemical structure, particularly in regard to its alkoxy group and the length of the alkyl chains at the acyl group, we synthesized two derivatives of DIF-3, 1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)octan-1-one (DIF-3(+3)) and 1-(3-chloro-2,6-dihydroxy-4-butoxyphenyl)-hexan1-one (Hex-DIF-3), and investigated their biological activities in vitro. At micro-molar levels, DIF-3(+3) and Hex-DIF-3 exhibited strong anti-proliferative effects in tumor cell cultures, but their anti-T. cruzi activities at 1 mu m in vitro were not as strong as those of other known DIF derivatives. In addition, Hex-DIF-3 at 5 mu m significantly suppressed mitogen-induced interleukin-2 production in vitro in Jurkat T cells. These results suggest that DIF-3(+3) and Hex-DIF-3 are promising leads for the development of anti-cancer and immunosuppressive agents.

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Targeting Prolyl-tRNA Synthetase to Accelerate Drug Discovery against Malaria, Leishmaniasis, Toxoplasmosis, Cryptosporidiosis, and Coccidiosis

Vitul Jain, Manickam Yogavel, Haruhisa Kikuchi, Yoshiteru Oshima, Norimitsu Hariguchi, Makoto Matsumoto, Preeti Goel, Bastien Touquet, Rajiv S. Jumani, Fabienne Tacchini-Cottier, Karl Harlos, Christopher D. Huston, Mohamed-Ali Hakimi, Amit Sharma

STRUCTURE (CELL PRESS) 25 ( 10 ) 1495 - + 2017.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 0969-2126

Developing anti-parasitic lead compounds that act on key vulnerabilities are necessary for new anti-infectives. Malaria, leishmaniasis, toxoplasmosis, cryptosporidiosis and coccidiosis together kill > 500,000 humans annually. Their causative parasites Plasmodium, Leishmania, Toxoplasma, Cryptosporidium and Eimeria display high conservation in many housekeeping genes, suggesting that these parasites can be attacked by targeting invariant essential proteins. Here, we describe selective and potent inhibition of prolyl-tRNA synthetases (PRSs) from the above parasites using a series of quinazolinone-scaffold compounds. Our PRS-drug co-crystal structures reveal remarkable active site plasticity that accommodates diversely substituted compounds, an enzymatic feature that can be leveraged for refining drug-like properties of quinazolinones on a per parasite basis. A compound we termed In-5 exhibited a unique double conformation, enhanced drug-like properties, and cleared malaria in mice. It thus represents a new lead for optimization. Collectively, our data offer insights into the structure-guided optimization of quinazolinone-based compounds for drug development against multiple human eukaryotic pathogens.

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