Donald Muccio

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Organization: University of Alabama at Birmingham

Department: Departments of Chemistry, Biochemistry and Molecular Genetics, §Medicine, and ∥Vision Sciences

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Chemicals
References

Conformationally Defined Rexinoids and Their Efficacy in the Prevention of Mammary Cancers

Co-reporter:Venkatram R. Atigadda; Gang Xia; Anil Deshpande; Lizhi Wu; Natalia Kedishvili; Craig D. Smith; Helen Krontiras; Kirby I. Bland; Clinton J. Grubbs; Wayne J. Brouillette;Donald D. Muccio

Journal of Medicinal Chemistry 2015 Volume 58(Issue 19) pp:7763-7774

Publication Date(Web):September 2, 2015

DOI:10.1021/acs.jmedchem.5b00829

(2E,4E,6Z,8Z)-8-(3′,4′-Dihydro-1′(2H)-naphthalen-1′-ylidene)-3,7-dimethyl-2,3,6-octatrienoinic acid (UAB30) is currently undergoing clinical evaluation as a novel cancer prevention agent. In efforts to develop even more highly potent rexinoids that prevent breast cancer without toxicity, we further explore here the structure–activity relationship of two separate classes of rexinoids. UAB30 belongs to the class II rexinoids and possesses a 9Z-tetraenoic acid chain bonded to a tetralone ring, whereas the class I rexinoids contain the same 9Z-tetraenoic acid chain bonded to a disubstituted cyclohexenyl ring. Among the 12 class I and class II rexinoids evaluated, the class I rexinoid 11 is most effective in preventing breast cancers in an in vivo rat model alone or in combination with tamoxifen. Rexinoid 11 also reduces the size of established tumors and exhibits a therapeutic effect. However, 11 induces hypertriglyceridemia at its effective dose. On the other hand rexinoid 10 does not increase triglyceride levels while being effective in the in vivo chemoprevention assay. X-ray studies of four rexinoids bound to the ligand binding domain of the retinoid X receptor reveal key structural aspects that enhance potency as well as those that enhance the synthesis of lipids.

Methyl Substitution of a Rexinoid Agonist Improves Potency and Reveals Site of Lipid Toxicity

Co-reporter:Venkatram R. Atigadda ; Gang Xia ; Anil Desphande ; LeeAnn J. Boerma ; Susan Lobo-Ruppert ; Clinton J. Grubbs ; Craig D. Smith ; Wayne J. Brouillette ;Donald D. Muccio

Journal of Medicinal Chemistry 2014 Volume 57(Issue 12) pp:5370-5380

Publication Date(Web):May 6, 2014

DOI:10.1021/jm5004792

(2E,4E,6Z,8E)-8-(3′,4′-Dihydro-1′(2′H)-naphthalen-1′-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid, 9cUAB30, is a selective rexinoid that displays substantial chemopreventive capacity with little toxicity. 4-Methyl-UAB30, an analogue of 9cUAB30, is a potent RXR agonist but caused increased lipid biosynthesis unlike 9cUAB30. To evaluate how methyl substitution influenced potency and lipid biosynthesis, we synthesized four 9cUAB30 homologues with methyl substitutions at the 5-, 6-, 7-, or 8-position of the tetralone ring. The syntheses and biological evaluations of these new analogues are reported here along with the X-ray crystal structures of each homologue bound to the ligand binding domain of hRXRα. We demonstrate that each homologue of 9cUAB30 is a more potent agonist, but only the 7-methyl-9cUAB30 caused severe hyperlipidemia in rats. On the basis of the X-ray crystal structures of these new rexinoids and bexarotene (Targretin) bound to hRXRα-LBD, we reveal that each rexinoid, which induced hyperlipidemia, had methyl groups that interacted with helix 7 residues of the LBD.

Methyl-substituted conformationally constrained rexinoid agonists for the retinoid X receptors demonstrate improved efficacy for cancer therapy and prevention

Co-reporter:Anil Desphande, Gang Xia, LeeAnn J. Boerma, Kimberly K. Vines, Venkatram R. Atigadda, Susan Lobo-Ruppert, Clinton J. Grubbs, Fariba L. Moeinpour, Craig D. Smith, Konstantin Christov, Wayne J. Brouillette, Donald D. Muccio

Bioorganic & Medicinal Chemistry 2014 Volume 22(Issue 1) pp:178-185

Publication Date(Web):1 January 2014

DOI:10.1016/j.bmc.2013.11.039

(2E,4E,6Z,8Z)-8-(3′,4′-Dihydro-1′(2H)-naphthalen-1′-ylidene)-3,7-dimethyl-2,3,6-octatrienoinic acid, 9cUAB30, is a selective rexinoid for the retinoid X nuclear receptors (RXR). 9cUAB30 displays substantial chemopreventive capacity with little toxicity and is being translated to the clinic as a novel cancer prevention agent. To improve on the potency of 9cUAB30, we synthesized 4-methyl analogs of 9cUAB30, which introduced chirality at the 4-position of the tetralone ring. The syntheses and biological evaluations of the racemic homolog and enantiomers are reported. We demonstrate that the S-enantiomer is the most potent and least toxic even though these enantiomers bind in a similar conformation in the ligand binding domain of RXR.

Structure, Energetics, and Dynamics of Binding Coactivator Peptide to the Human Retinoid X Receptor α Ligand Binding Domain Complex with 9-cis-Retinoic Acid

Co-reporter:Gang Xia, LeeAnn J. Boerma, Bryan D. Cox, Cheng Qiu, Sebyung Kang, Craig D. Smith, Matthew B. Renfrow, and Donald D. Muccio

Biochemistry 2011 Volume 50(Issue 1) pp:

Publication Date(Web):November 4, 2010

DOI:10.1021/bi101288y

Retinoid X receptors (RXRs) are ligand-dependent nuclear receptors, which are activated by the potent agonist 9-cis-retinoic acid (9cRA). 9cRA binds to the ligand binding domain (LBD) of RXRs and recruits coactivator proteins for gene transcription. Using isothermal titration calorimetry, the binding of a 13-mer coactivator peptide, GRIP-1, to the hRXRα-LBD homodimer complex containing 9cRA (hRXRα-LBD:9cRA:GRIP-1) is reported between 20 and 37 °C. ΔG is temperature independent (−8.5 kcal/mol), and GRIP-1 binding is driven by ΔH (−9.2 kcal/mol) at 25 °C. ΔCp is large and negative (−401 cal mol−1 K−1). The crystal structure of hRXRα-LBD:9cRA:GRIP-1 is reported at 2.05 Å. When the structures of hRXRα-LBD:9cRA:GRIP-1 and hRXRα-LBD:9cRA (1FBY) homodimers are compared, E453 and E456 on helix 12 bury and form ionic interactions with GRIP-1. R302 on helix 4 realigns to form new salt bridges to both E453 and E456. F277 (helix 3), F437 (helix 11), and F450 (helix 12) move toward the hydrophobic interior. The changes in the near-UV spectrum at 260 nm of the hRXRα-LBD:9cRA:GRIP-1 support this structural change. Helix 11 tilts toward helix 12 by ≈1 Å, modifying the ring conformation of 9cRA. Hydrogen−deuterium exchange mass spectroscopy indicates GRIP-1 binding to hRXRα-LBD:9cRA significantly decreases the exchange rates for peptides containing helices 3 (F277), 4 (R302), 11 (F437), and 12 (E453, E456). The structural changes and loss of dynamics of the GRIP-1-bound structure are used to interpret the energetics of coactivator peptide binding to the agonist-bound hRXRα-LBD.

NMR conformational analysis of cis and trans proline isomers in the neutrophil chemoattractant, N-acetyl–proline–glycine–proline

Co-reporter:Yi-Chien Lee;Patricia L. Jackson;Michael J. Jablonsky;Donald D. Muccio;Roswell R. Pfister;Jeffrey L. Haddox;Charnell I. Sommers;G. M. Anantharamaiah;Manjula Chaddha

Biopolymers 2001 Volume 58(Issue 6) pp:

Publication Date(Web):2 MAR 2001

DOI:10.1002/1097-0282(200105)58:6<548::AID-BIP1030>3.0.CO;2-B

Alkaline hydrolysis of corneal proteins in the alkali-injured eye releases N-acetyl–proline–glycine–proline (Ac–Pro–Gly–Pro–OH) among other peptides. It has been shown that this tripeptide is a neutrophil chemoattractant. Existing data suggest that the release of this peptide is the catalytic event for early neutrophil invasion of the cornea leading to corneal ulcers. In order to design inhibitors of this tripeptide chemoattractant that would block neutrophil invasion and diminish corneal ulcers, we studied the solution properties of this tripeptide by NMR spectroscopy and compared this peptide to Ac–Pro–Gly–OH (a weaker chemoattractant), and to Ac–Pro–OH (inactive). The NMR data were consistent with Ac–Pro–Gly–Pro–OH existing in solution as a mixture of four isomers with different cis and trans conformations about the two X–proline amide bonds. The isomer with two trans conformations (trans–trans) was the most dominant (41%) in aqueous solution. This was followed by the isomers with mixed cis and trans conformations (trans–cis, 26% and cis–trans, 20%). The isomer with two cis conformations (cis–cis) was the least favored (13%). The populations of these isomers were investigated in DMSO and they were similar to those reported in aqueous solutions except that the ordering of the trans–cis and cis–trans isomers were reversed. NMR NH temperature coefficients and nuclear Overhauser effect (NOE) measurements as well as CD spectroscopy were used to demonstrate that the four isomers exist primarily in an extended conformation with little hydrogen bonding. The available (NOE) information was used with molecular dynamics calculations to construct a dominant solution conformation for each isomer of the tripeptide. This information will serve as a model for the design of peptide and nonpeptide inhibitors of the chemoattractant. © 2001 John Wiley & Sons, Inc. Biopolymers 58: 548–561, 2001

1H and 13C NMR assignments of conformationally defined 6- s-cis-retinoids

Co-reporter:Y. C. Lee;W. J. Brouillette;D. D. Muccio;M. Alam

Magnetic Resonance in Chemistry 1999 Volume 37(Issue 1) pp:82-85

Publication Date(Web):13 JAN 1999

DOI:10.1002/(SICI)1097-458X(199901)37:1<82::AID-MRC381>3.0.CO;2-M

Three examples of a new class of retinoic acid analogs (retinoids) were synthesized. These retinoids contain a dimethylene bridge to maintain a 6-s-cis conformation of the terminal double bonds, which is preferred in the major conformation of the natural compound. The ¹H and ¹³C NMR spectra were assigned for 22 new compounds, including retinoid E/Z isomers (all- E, 13Z, 9Z) and selected intermediates. The assignments were based upon long-range ¹H– ¹³C heteronuclear 2D experiments. © 1999 John Wiley & Sons, Ltd.