Inhibition of Lymphocyte Kinase Lck and Phosphatidylinositol 3-kinase by a Novel Immunosuppressant, Lymphostin

Nagata, Hiroyuki; Yano, Hiroshi; Sasaki, Kimihito; Sato, Soichiro; Nakanishi, Satoshi; Takahashi, Isami; Tamaoki, Tatsuya

doi:10.1271/bbb.66.501

Cited by 13 publications

(11 citation statements)

References 30 publications

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“…Later, it was revealed that the efficacy of lymphostin in blocking mixed lymphocyte reaction and delayed-type hypersensitivity was actually due to the dual inhibition of LCK and phosphoinositide 3-kinase (PI3K) (IC 50 : 1 nM). 27 Very recently, lymphostin was shown to be a potent mTOR inhibitor (IC 50 : 1.7 nM). 28 It is likely that the binding mode of lymphostin mimics that of olomoucine in the hinge region.…”

Section: Purine Analoguesmentioning

confidence: 99%

Natural products as kinase inhibitors

Liu

Waller

et al. 2012

Nat. Prod. Rep.

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Natural products have been widely used to dissect the basic mechanisms of fundamental life science and as clinical therapeutics. Recently, there has been significant interest in discovering new chemical pharmacophores in natural products to fulfil the vast demand for novel kinase inhibitors and address critical unmet medical needs with respect to signal transduction pathways. In this review, we summarize the history of several different classes of natural product-derived kinase inhibitors, discuss their kinome-wide target profiles and examine their structural binding modes based on available 3D X-ray structures. In particular, their origin, target activity, selectivity, scope and potential therapeutic development are highlighted against the backdrop of medicinal chemistry.

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Section: Purine Analoguesmentioning

confidence: 99%

Natural products as kinase inhibitors

Liu

Waller

et al. 2012

Nat. Prod. Rep.

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“…This framework is now considered to be created by ribosomally synthesized and post-translationally modified peptide (RiPP) pathways delivering a C-terminal tryptophan building block [16]. The compilation in Figure 1 also abstracts therapeutic assessment outcomes for eight different lead structures [8,9,10,11,12,13,14,15,17,18,19,20,21,22]. Two sponge genera, Zyzzya and Latrunculia , [23] are abundant sources of pyrrolo[4,3,2- de ]quinolines which now number close to 100 structures.…”

Section: Introductionmentioning

confidence: 99%

“…Mushrooms produce further functionalized core skeletons represented by sanguinone A [18] and mycenarubin A [17]. Marine-derived Gram-positive microorganisms are the source of: (a) ammosamides [19,20] possessing halogen substituents; and (b) lymphostins [21,22] containing additional residues created by PKS biosynthesis. While several of the compounds in Figure 1 inhibit druggable cancer targets few of them shown here or elsewhere exhibit single or double digit nanomolar in vitro potency.…”

Section: Introductionmentioning

confidence: 99%

Another Look at Pyrroloiminoquinone Alkaloids—Perspectives on Their Therapeutic Potential from Known Structures and Semisynthetic Analogues

et al. 2017

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This study began with the goal of identifying constituents from Zyzzya fuliginosa extracts that showed selectivity in our primary cytotoxicity screen against the PANC-1 tumor cell line. During the course of this project, which focused on six Z. fuliginosa samples collected from various regions of the Indo-Pacific, known compounds were obtained consisting of nine makaluvamine and three damirone analogues. Four new acetylated derivatives were also prepared. High-accuracy electrospray ionization mass spectrometry (HAESI-MS) m/z ions produced through MS2 runs were obtained and interpreted to provide a rapid way for dereplicating isomers containing a pyrrolo[4,3,2-de]quinoline core. In vitro human pancreas/duct epithelioid carcinoma (PANC-1) cell line IC50 data was obtained for 16 compounds and two therapeutic standards. These results along with data gleaned from the literature provided useful structure activity relationship conclusions. Three structural motifs proved to be important in maximizing potency against PANC-1: (i) conjugation within the core of the ABC-ring; (ii) the presence of a positive charge in the C-ring; and (iii) inclusion of a 4-ethyl phenol or 4-ethyl phenol acetate substituent off the B-ring. Two compounds, makaluvamine J (9) and 15-O-acetyl makaluvamine J (15), contained all three of these frameworks and exhibited the best potency with IC50 values of 54 nM and 81 nM, respectively. These two most potent analogs were then tested against the OVCAR-5 cell line and the presence of the acetyl group increased the potency 14-fold from that of 9 whose IC50 = 120 nM vs. that of 15 having IC50 = 8.6 nM.

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“…The pyrrolo[4,3,2- de ]quinoline core represents a characteristic motif of many natural alkaloids that exhibit a wide range of biological activities, including potent cytotoxicity and pharmacological activity . Shown in Figure are some typical examples of pyrroloquinoline alkaloids with attractive bioactivities. − Isolated early from marine sponges, discorhabdin C possesses potent cytotoxicities against several cancer cell lines such as murine leukemia cells P388 and L1210 and human colon cancer cells HCT-116 . Lymphostin as a natural immunosuppressant was first isolated from bacteria Streptomyces sp.…”

mentioning

confidence: 99%

“…Lymphostin as a natural immunosuppressant was first isolated from bacteria Streptomyces sp. KY11783 and exhibits potent inhibitory activities against lymphocyte kinase (IC 50 0.05 μM) and phosphatidylinositol 3-kinase (IC 50 0.001 μM) . Recently isolated from marine bacteria Streptomyces strain CNR-698, ammosamides A–C as new members of pyrroloquinoline alkaloids are able to influence tubulin and actin dynamics through myosin targeting .…”

mentioning

confidence: 99%

Annulation Reaction of 3-Acylmethylidene Oxindoles with Huisgen Zwitterions and Its Applications in the Syntheses of Pyrrolo[4,3,2-de]quinolinones and Marine Alkaloids Ammosamides

et al. 2016

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A novel annulation reaction of 3-acylmethylidene oxindoles with Huisgen zwitterions is unveiled that leads to an unprecedented synthetic method for complex pyrrolo[4,3,2-de]quinolinones and marine alkaloids ammosamides A-C. This method features simplicity, high efficiency, and broad substrate scope and is accordingly anticipated to significantly facilitate the preparation and bioassay of the relevant pyrroloquinoline alkaloids and their analogues.

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Inhibition of Lymphocyte Kinase Lck and Phosphatidylinositol 3-kinase by a Novel Immunosuppressant, Lymphostin

Cited by 13 publications

References 30 publications

Natural products as kinase inhibitors

Natural products as kinase inhibitors

Another Look at Pyrroloiminoquinone Alkaloids—Perspectives on Their Therapeutic Potential from Known Structures and Semisynthetic Analogues

Annulation Reaction of 3-Acylmethylidene Oxindoles with Huisgen Zwitterions and Its Applications in the Syntheses of Pyrrolo[4,3,2-de]quinolinones and Marine Alkaloids Ammosamides

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