A Concise Synthesis of Mupirocin H Using a Cross‐Metathesis‐Based Strategy

Sengupta, Sandip,Sim, Taebo WILEY‐VCH Verlag 2014 EUROPEAN JOURNAL OF ORGANIC CHEMISTRY Vol.2014 No.23

<P><B>Abstract</B></P><P>A highly efficient (10.1 % overall yield) and convergent (longest linear sequence of 16 steps) synthesis of mupirocin H has been achieved, starting from commercially available (+)‐(<I>R</I>)‐Roche ester. The route relies on an efficient Grubbs cross‐metathesis reaction to generate a key, late‐stage <I>E</I>‐olefin intermediate, and a cobalt‐catalysed diastereoselective Reformatsky reaction to produce a β‐hydroxy ester that serves as a late‐stage intermediate.</P>

A Concise and Efficient Total Synthesis of Militarinone D

Dash, Uttam,Sengupta, Sandip,Sim, Taebo WILEY‐VCH Verlag 2015 EUROPEAN JOURNAL OF ORGANIC CHEMISTRY Vol.2015 No.18

<P><B>Abstract</B></P><P>A highly stereoselective, concise (14 steps longest linear sequence and 20 steps overall), and efficient (15 % overall yield) synthesis of militarinone D has been accomplished. The key reactions utilized in the sequence are enzymatic desymmetrization, <I>cis</I>/<I>trans</I> isomerization, Horner–Wadsworth–Emmons olefination, and addition of an organolithium species to a highly conjugated chiral aldehyde. The simplicity of the strategy may enable its utilization in the large‐scale production of this target. Moreover, the strategy utilized to design the route should be applicable to the preparation of analogs that bear a variety of substituted pyridinone core structures.</P>

A new quantum dot–platinum conjugate for self-assembled nanoconjugates by coordination bonding mediated recognition

Lee, Jiyeon,Kim, Heeyeon,Sim, Taebo,Song, Rita The Royal Society of Chemistry 2013 Chemical communications Vol.49 No.55

<P>A new binding strategy of linking quantum dots (QDs) to magnetic nanoparticles (MNPs) using DNA interaction with metal coordination bonding was developed. Platinum was selected for binding QDs to DNA. This novel self-assembled nanoconjugate would be a new probe for diagnosing a specific disease more accurately with its double modalities, fluorescence and magnetic property.</P> <P>Graphic Abstract</P><P>A new self-assembled nanoconjugate was prepared using a quantum dot–platinum complex and DNA modified magnetic nanoparticles. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=c3cc42245c'> </P>

One step synthesis of quantum dot–magnetic nanoparticle heterodimers for dual modal imaging applications

Lee, Jiyeon,Hwang, Gyoyeon,Hong, Yeon Sun,Sim, Taebo The Royal Society of Chemistry 2015 The Analyst Vol.140 No.8

<P>Dual modal nanoprobes are promising tools for accurately detecting target molecules as part of the diagnosis of diseases including cancers. We have explored a new dual modal bioimaging probe that is comprised of a quantum dot (QD)-magnetic nanoparticle (MNP) hybrid. The MNP-QD heterodimers explored are fabricated by using a platinum-guanine coordination bonding guided self-assembly process, employing the metal-DNA conjugation method. Investigations utilizing energy dispersive spectroscopy (EDS) equipped high resolution transmission electron microscopy (HRTEM) demonstrate that the heterodimer contains an iron (Fe) dominant MNP and a cadmium (Cd) dominant QD. Finally, the results of cell studies show that the MNP-QD conjugates display good HeLa cell uptake in the absence of non-specific binding to the cell membrane and, as such, they can be used to label cells in vitro and in vivo as part of a new cell imaging technique.</P>

Antitumor Effects and Mechanisms of AZD4547 on FGFR2-Deregulated Endometrial Cancer Cells

Kwak, Yeonui,Cho, Hanna,Hur, Wooyoung,Sim, Taebo American Association for Cancer Research 2015 Molecular Cancer Therapeutics Vol.14 No.10

<P>Uncontrolled activation of FGFRs induces the progression of various cancers. It was recently reported that FGFR2-activating mutants are implicated in about 12% of endometrial carcinomas. AZD4547, a potent pan-FGFR inhibitor, is currently being evaluated in clinical trials for several FGFR-driven cancers. However, AZD4547 has not been examined yet against FGFR2 mutant-driven endometrial cancers. Thus, we evaluated the activity of AZD4547 against four different endometrial cancer cells, including AN3-CA, MFE296, MFE280, and HEC1A, where all but HEC1A cells express distinctive FGFR2 mutations. We found that AZD4547 exhibits potent antiproliferative activity (EC50 + 31 nmol/L) against AN3-CA cells harboring FGFR2-K310R/N550K mutant. Analysis using a phospho-kinase array revealed that AZD4547 blocks FGFR2 downstream signaling, such as p38, ERK1/2, JNK, p70S6K, and PLCg. Moreover, oral administration of AZD4547 (30 mg/kg, every day) remarkably delayed tumor growth in a mouse xenograft model of AN3-CA cells. Unbiased reporter gene assay showed that AZD4547 antagonizes the aFGF-induced activation of several transcription factors, including EGR1, ELK-1/SRF, AP-1, and NF kappa B. Genome-wide transcriptome analysis revealed that AZD4547 perturbs a number of transcriptions, and EGR1 was identified as one of the major targets of AZD4547. The significance of the FGFR2-EGR1 axis in endometrial cancer progression has not been reported. In addition, using kinome-wide inhibition profiling analysis, we first identified potential new target kinases of AZD4547, including MAP4K3, MAP4K5, IRR, RET, and FLT3. Our study demonstrated that AZD4547 exhibits its therapeutic activity against endometrial cancer cells by perturbing various regulatory mechanisms related to FGFR signaling. (C) 2015 AACR.</P>

Development of ‘DFG-out’ inhibitors of gatekeeper mutant kinases

Choi, Hwan Geun,Zhang, Jianming,Weisberg, Ellen,Griffin, James D.,Sim, Taebo,Gray, Nathanael S. Elsevier 2012 Bioorganic & medicinal chemistry letters Vol.22 No.16

Pharmacophore based 3D-QSAR study of VEGFR-2 inhibitors

Neaz, M. M.,Pasha, F. A.,Muddassar, M.,Lee, So Ha,Sim, Taebo,Hah, Jung-Mi,Cho, Seung Joo Springer-Verlag 2009 MEDICINAL CHEMISTRY RESEARCH Vol.18 No.2

Design, synthesis, and biological evaluation of novel aminopyrimidinylisoindolines as AXL kinase inhibitors

Choi, Min Jung,Roh, Eun Joo,Hur, Wooyoung,Lee, So Ha,Sim, Taebo,Oh, Chang-Hyun,Lee, Sun-Hwa,Kim, Jong Seung,Yoo, Kyung Ho Elsevier 2018 Bioorganic & medicinal chemistry letters Vol.28 No.23

<P><B>Abstract</B></P> <P>A novel series of aminopyrimidinylisoindoline derivatives <B>1a-w</B> having an aminopyrimidine scaffold as a hinge region binding motif were designed and synthesized. Among them, six compounds showed potent inhibitory activities against AXL kinase with IC<SUB>50</SUB> values of submicromolar range. Especially, compound <B>1u</B> possessing (4-acetylpiperazin-1-yl)phenyl moiety exhibited extremely excellent efficacy (IC<SUB>50</SUB> = <0.00050 μM). Their <I>in vitro</I> antiproliferative activities were tested over five cancer cell lines. Most compounds showed good antiproliferative activities against HeLa cell line. The kinase panel profiling of 50 different kinases and the selected inhibitory activities for the representative compound <B>1u</B> were carried out. The compound <B>1u</B> exhibited excellent inhibitory activities (IC<SUB>50</SUB> = <0.00050, 0.025, and 0.050 μM for AXL, MER, and TYRO3, respectively) against TAM family, together with potent antiproliferative activity against MV4-11 cell line (GI<SUB>50</SUB> = 0.10 μM) related to acute myeloid leukemia (AML).</P> <P><B>Highlights</B></P> <P> <UL> <LI> Six compounds showed potent inhibitory activities against AXL kinase. </LI> <LI> Most compounds showed good antiproliferative activities against HeLa cell line. </LI> <LI> <B>1u</B> exhibited extremely excellent efficacy (IC<SUB>50</SUB> = <0.00050 μM) against AXL kinase. </LI> <LI> <B>1u</B> showed the best combination of enzyme inhibitory and antiproliferative activities. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Antitumor effects and molecular mechanisms of ponatinib on endometrial cancer cells harboring activating FGFR2 mutations

Kim, Do-Hee,Kwak, Yeonui,Kim, Nam Doo,Sim, Taebo LANDES BIOSCIENCE 2016 Cancer Biology & Therapy Vol.17 No.1

<P>Aberrant mutational activation of FGFR2 is associated with endometrial cancers (ECs). AP24534 (ponatinib) currently undergoing clinical trials has been known to be an orally available multi-targeted tyrosine kinase inhibitor. Our biochemical kinase assay showed that AP24534 is potent against wild-type FGFR1-4 and 5 mutant FGFRs (V561M-FGFR1, N549H-FGFR2, K650E-FGFR3, G697C-FGFR3, N535K-FGFR4) and possesses the strongest kinase-inhibitory activity on N549H-FGFR2 (IC50 of 0.5nM) among all FGFRs tested. We therefore investigated the effects of AP24534 on endometrial cancer cells harboring activating FGFR2 mutations and explored the underlying molecular mechanisms. AP24534 significantly inhibited the proliferation of endometrial cancer cells bearing activating FGFR2 mutations (N549K, K310R/N549K, S252W) and mainly induced G1/S cell cycle arrest leading to apoptosis. AP24534 also diminished the kinase activity of immunoprecipitated FGFR2 derived from MFE-296 and MFE-280 cells and reduced the phosphorylation of FGFR2 and FRS2 on MFE-296 and AN3CA cells. AP24534 caused substantial reductions in ERK phosphorylation, PLC signaling and STAT5 signal transduction on ECs bearing FGFR2 activating mutations. Akt signaling pathway was also deactivated by AP24534. AP24534 causes the chemotherapeutic effect through mainly the blockade of ERK, PLC and STAT5 signal transduction on ECs. Moreover, AP24534 inhibited migration and invasion of endometrial cancer cells with FGFR2 mutations. In addition, AP24534 significantly blocked anchorage-independent growth of endometrial cancer cells. We, for the first time, report the molecular mechanisms by which AP24534 exerts antitumor effects on ECs with FGFR2 activating mutations, which would provide mechanistic insight into ongoing clinical investigations of AP24534 for ECs.</P>

Targeting Bcr–Abl by combining allosteric with ATP-binding-site inhibitors

Zhang, Jianming,Adriá,n, Francisco J.,Jahnke, Wolfgang,Cowan-Jacob, Sandra W.,Li, Allen G.,Iacob, Roxana E.,Sim, Taebo,Powers, John,Dierks, Christine,Sun, Fangxian,Guo, Gui-Rong,Ding, Qiang,Okra Macmillan Publishers Limited. All rights reserved 2010 Nature Vol.463 No.7280

In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr–Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr–Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr–Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model. These results show that therapeutically relevant inhibition of Bcr–Abl activity can be achieved with inhibitors that bind to the myristate-binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.