Fluorescent probes of the isoxazole-dihydropyridine scaffold: MDR-1 binding and homology model Dedicated to the memory of Professor Robert O. Hutchins, peerless mentor and good friend

Monika I. Szabon-Watola; Sarah V. Ulatowski; Kathleen M. George; Christina D. Hayes; Scott A. Steiger; Nicholas R. Natale

doi:10.1016/j.bmcl.2013.11.068

Fluorescent probes of the isoxazole-dihydropyridine scaffold: MDR-1 binding and homology model Dedicated to the memory of Professor Robert O. Hutchins, peerless mentor and good friend

Monika I. Szabon-Watola, Sarah V. Ulatowski, Kathleen M. George, Christina D. Hayes, Scott A. Steiger, Nicholas R. Natale

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Isoxazole-1,4-dihydropyridines (IDHPs) were tethered to fluorescent moieties using double activation via a lanthanide assisted Weinreb amidation. IDHP-fluorophore conjugate 3c exhibits the highest binding to date for IDHPs at the multidrug-resistance transporter (MDR-1), and IDHP-fluorophore conjugates 3c and 7 distribute selectively in SH-SY5Y cells. A homology model for IDHP binding at MDR-1 is presented which represents our current working hypothesis.

Original language	English
Pages (from-to)	117-121
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	24
Issue number	1
DOIs	https://doi.org/10.1016/j.bmcl.2013.11.068
State	Published - Jan 1 2014

Funding

MDR1 data was generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program (NIMH PDSP) , Contract # HHSN-271-2008-00025-C (NIMH PDSP). The NIMH PDSP is Directed by Bryan L. Roth MD, Ph.D. at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA. The authors thank NIH for grants NS038444 (N.N., M.I.S.), 5U01ES016102-02 (K.M.G., S.V.U.), and P20RR015583 (N.N., S.S.). C.D.H. thanks the NSF REU Award Number 0649306 . M.I.S. thanks the Malcolm and Carol Renfrew Scholarship. We thank Dr. Alex Blumenfeld for VT NMR and Dr. Gary Knerr for able assistance in FAB MS while at the University of Idaho. We thank Dr. Mike Braden and Dave Holley of the Core Facility for Molecular Computation (UM) for helpful discussions during pharmacophore modeling.

Funder number
0649306
HHSN-271-2008-00025-C
P20RR015583

Keywords

Dihydropyridine
Homology model
Isoxazole
Multidrug resistance transporter

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10.1016/j.bmcl.2013.11.068

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Szabon-Watola, M. I., Ulatowski, S. V., George, K. M., Hayes, C. D., Steiger, S. A., & Natale, N. R. (2014). Fluorescent probes of the isoxazole-dihydropyridine scaffold: MDR-1 binding and homology model Dedicated to the memory of Professor Robert O. Hutchins, peerless mentor and good friend. Bioorganic and Medicinal Chemistry Letters, 24(1), 117-121. https://doi.org/10.1016/j.bmcl.2013.11.068

@article{e94a5aaa455c47288f550a31cb14e1aa,

title = "Fluorescent probes of the isoxazole-dihydropyridine scaffold: MDR-1 binding and homology model Dedicated to the memory of Professor Robert O. Hutchins, peerless mentor and good friend",

abstract = "Isoxazole-1,4-dihydropyridines (IDHPs) were tethered to fluorescent moieties using double activation via a lanthanide assisted Weinreb amidation. IDHP-fluorophore conjugate 3c exhibits the highest binding to date for IDHPs at the multidrug-resistance transporter (MDR-1), and IDHP-fluorophore conjugates 3c and 7 distribute selectively in SH-SY5Y cells. A homology model for IDHP binding at MDR-1 is presented which represents our current working hypothesis.",

keywords = "Dihydropyridine, Homology model, Isoxazole, Multidrug resistance transporter",

author = "Szabon-Watola, \{Monika I.\} and Ulatowski, \{Sarah V.\} and George, \{Kathleen M.\} and Hayes, \{Christina D.\} and Steiger, \{Scott A.\} and Natale, \{Nicholas R.\}",

note = "Funding Information: MDR1 data was generously provided by the National Institute of Mental Health{\textquoteright}s Psychoactive Drug Screening Program (NIMH PDSP) , Contract \# HHSN-271-2008-00025-C (NIMH PDSP). The NIMH PDSP is Directed by Bryan L. Roth MD, Ph.D. at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA. Funding Information: The authors thank NIH for grants NS038444 (N.N., M.I.S.), 5U01ES016102-02 (K.M.G., S.V.U.), and P20RR015583 (N.N., S.S.). C.D.H. thanks the NSF REU Award Number 0649306 . M.I.S. thanks the Malcolm and Carol Renfrew Scholarship. We thank Dr. Alex Blumenfeld for VT NMR and Dr. Gary Knerr for able assistance in FAB MS while at the University of Idaho. We thank Dr. Mike Braden and Dave Holley of the Core Facility for Molecular Computation (UM) for helpful discussions during pharmacophore modeling. ",

year = "2014",

month = jan,

day = "1",

doi = "10.1016/j.bmcl.2013.11.068",

language = "English",

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pages = "117--121",

journal = "Bioorganic and Medicinal Chemistry Letters",

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Szabon-Watola, MI, Ulatowski, SV, George, KM, Hayes, CD, Steiger, SA & Natale, NR 2014, 'Fluorescent probes of the isoxazole-dihydropyridine scaffold: MDR-1 binding and homology model Dedicated to the memory of Professor Robert O. Hutchins, peerless mentor and good friend', Bioorganic and Medicinal Chemistry Letters, vol. 24, no. 1, pp. 117-121. https://doi.org/10.1016/j.bmcl.2013.11.068

Fluorescent probes of the isoxazole-dihydropyridine scaffold: MDR-1 binding and homology model Dedicated to the memory of Professor Robert O. Hutchins, peerless mentor and good friend. / Szabon-Watola, Monika I.; Ulatowski, Sarah V.; George, Kathleen M. et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 24, No. 1, 01.01.2014, p. 117-121.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Fluorescent probes of the isoxazole-dihydropyridine scaffold

T2 - MDR-1 binding and homology model Dedicated to the memory of Professor Robert O. Hutchins, peerless mentor and good friend

AU - Szabon-Watola, Monika I.

AU - Ulatowski, Sarah V.

AU - George, Kathleen M.

AU - Hayes, Christina D.

AU - Steiger, Scott A.

AU - Natale, Nicholas R.

N1 - Funding Information: MDR1 data was generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program (NIMH PDSP) , Contract # HHSN-271-2008-00025-C (NIMH PDSP). The NIMH PDSP is Directed by Bryan L. Roth MD, Ph.D. at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA. Funding Information: The authors thank NIH for grants NS038444 (N.N., M.I.S.), 5U01ES016102-02 (K.M.G., S.V.U.), and P20RR015583 (N.N., S.S.). C.D.H. thanks the NSF REU Award Number 0649306 . M.I.S. thanks the Malcolm and Carol Renfrew Scholarship. We thank Dr. Alex Blumenfeld for VT NMR and Dr. Gary Knerr for able assistance in FAB MS while at the University of Idaho. We thank Dr. Mike Braden and Dave Holley of the Core Facility for Molecular Computation (UM) for helpful discussions during pharmacophore modeling.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Isoxazole-1,4-dihydropyridines (IDHPs) were tethered to fluorescent moieties using double activation via a lanthanide assisted Weinreb amidation. IDHP-fluorophore conjugate 3c exhibits the highest binding to date for IDHPs at the multidrug-resistance transporter (MDR-1), and IDHP-fluorophore conjugates 3c and 7 distribute selectively in SH-SY5Y cells. A homology model for IDHP binding at MDR-1 is presented which represents our current working hypothesis.

AB - Isoxazole-1,4-dihydropyridines (IDHPs) were tethered to fluorescent moieties using double activation via a lanthanide assisted Weinreb amidation. IDHP-fluorophore conjugate 3c exhibits the highest binding to date for IDHPs at the multidrug-resistance transporter (MDR-1), and IDHP-fluorophore conjugates 3c and 7 distribute selectively in SH-SY5Y cells. A homology model for IDHP binding at MDR-1 is presented which represents our current working hypothesis.

KW - Dihydropyridine

KW - Homology model

KW - Isoxazole

KW - Multidrug resistance transporter

UR - https://www.scopus.com/pages/publications/84891496404

U2 - 10.1016/j.bmcl.2013.11.068

DO - 10.1016/j.bmcl.2013.11.068

M3 - Article

C2 - 24342237

AN - SCOPUS:84891496404

SN - 0960-894X

VL - 24

SP - 117

EP - 121

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 1

ER -

Fluorescent probes of the isoxazole-dihydropyridine scaffold: MDR-1 binding and homology model Dedicated to the memory of Professor Robert O. Hutchins, peerless mentor and good friend

Abstract

Funding

Keywords

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