66774-09-2Relevant academic research and scientific papers
The synthesis of novel p-quinone methides: O-dealkylation of 5-(p-alkyloxyaryl)-10,11-dihydrodibenzo[a,d]cyclohepten-5-ols and related compounds
Taljaard, Benjamin,Taljaard, Jana H.,Imrie, Christopher,Caira, Mino R.
, p. 2607 - 2619 (2005)
The synthesis of a series of novel tricyclic p-quinone methides (p-QMs) from 5-(p-alkyloxyaryl)-10,11-dihydrodibenzo[a,d]cyclohepten-5-ol and related substrates in moderate-to-good yields is reported. The reaction is proposed to proceed under mild acidic conditions by O-dealkylation of the p-alkoxy group on the p-position of the pendant 5-aryl ring on the B-ring of the tricyclic system.The effect of different alkyl groups on the oxygen atom, as well as substituent groups on the phenyl ring flanking the O-alkyl group has also been investigated The mechanism of the reaction is discussed in terms of the relatively high intermediate cation stabilities, the possible intermediacy of a hemiketal, as well as conformational effects. Various modifications to the central seven-membered B-ring to introduce more rigidity to the tricyclic system have been made and the scope of the reaction further elaborated. Furthermore, the single crystal structure of dienone 14 has been determined and the p-quinone methide shown to be non-planar, which would account for the relative conformational rigidity of these systems and their ability to accommodate the planar cyclohexa-2,5-dienone moiety and thus explain the stability of these systems relative to their 5- and six-membered B-ring counterparts. These compounds may be useful for the synthesis of novel dyes or compounds which may exhibit photochromic and thermochromic properties. ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005).
Design, synthesis, and evaluation of a novel prodrug, a S-trityl-L-cysteine derivative targeting kinesin spindle protein
Fukai, Ryota,Ogo, Naohisa,Ichida, Taiki,Yamane, Masayoshi,Sawada, Jun-ichi,Miyoshi, Nao,Murakami, Hisashi,Asai, Akira
, (2021)
Kinesin spindle protein (KSP) is expressed only in cells undergoing cell division, and hence represents an attractive target for the treatment of cancer. Several KSP inhibitors have been developed and undergone clinical trial, but their clinical use is limited by their toxicity to rapidly proliferating non-cancerous cells. To create new KSP inhibitors that are highly selective for cancer cells, we optimized the amino acid moiety of S-trityl-L-cysteine (STLC) derivative 1 using in silico modeling. Molecular docking and molecular dynamics simulation were performed to investigate the binding mode of 1 with KSP. Consistent with the structure activity relationship studies, we found that a cysteine amino moiety plays an important role in stabilizing the interaction. Based on these findings and the structure of GSH, a substrate of γ-glutamyltransferase (GGT), we designed and synthesized the prodrug N-γ-glutamylated STLC derivative 9, which could be hydrolyzed by GGT to produce 1. The KSP ATPase inhibitory activity of 9 was lower than that of 1, and LC-MS analysis indicated that 9 was converted to 1 only in the presence of GGT in vitro. In addition, the cytotoxic activity of 9 was significantly attenuated in GGT-knockdown A549 cells. Since GGT is overexpressed on the cell membrane of various cancer cells, these results suggest that compound 9 could be a promising prodrug that selectively inhibits the proliferation of GGT-expressing cancer cells.
Structure-guided design of novel l -Cysteine derivatives as potent KSP inhibitors
Ogo, Naohisa,Ishikawa, Yoshinobu,Sawada, Jun-Ichi,Matsuno, Kenji,Hashimoto, Akihiro,Asai, Akira
supporting information, p. 1004 - 1009 (2015/09/22)
Kinesin spindle protein (KSP), known as Hs Eg5, a member of the kinesin-5 family, plays an important role in the formation and maintenance of the bipolar spindle. We previously reported S-trityl-l-cysteine derivatives as selective KSP inhibitors. Here, we report further optimizations using docking modeling in the L5 allosteric binding site, which led to the discovery of several high affinity derivatives with two fused phenyl rings in the trityl group giving low nanomolar range KSP ATPase inhibition. The representative derivatives potently inhibited cell growth of HCT116 cells in correlation with KSP inhibitory activities and significantly suppressed tumor growth in the xenograft model in vivo.
New and its salt cysteines compd.
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Paragraph 0075, (2016/12/22)
The purpose of the present invention is to provide a novel compound with Eg5 inhibiting activity that is useful as an antitumoral agent. The present invention pertains to a compound expressed by the general formula (I) (in formula (I), A represents Ch2, a
