n - Indian Institute of Astrophysics

Thyroid Hormone SynthesisthyroglobulinHOHCHtyrosineHOHCHTPOI II IIHCHHCHTPOHOHOH 2 O 2 IIIODINEIHCHHOIIOthyroxineIIHCHRecommended Daily IntakeHOIOIHOOIIIT4E-Se-AuHCO 2 HNH 2GTGE-Se H +IIT3E-SeIPTUIHCO 2 HNH 2E SeSHNNThyroidOCH 2 CH 2 CH 3I + DTT oxDTT redHyperthyroidism – anti-thyroid drugsHumboldt Kolleg, IIA Bangalore, February 2-5, 2011

Selenenyl Iodide – Non-existent Compound?For a long time, uncharged covalent selenium iodides have been regarded as non-existent .W. E. Dasent, Nonexistent compounds, Marcel Dekker, New York (1965) .RSeRSeIsodesmic Equation+ I I 2 Se IRIISeSeSeSeII172 + 150 = 322 kJ/mol 2 x 150 = 300 kJ/molSeSeMe 3 Si SiMe 3SiMe 3trisylsupermesitylHumboldt Kolleg, IIA Bangalore, February 2-5, 2011du Mont, et al. Angew. Chem. Int. Ed. 1987, 26, 780.

Interactions of Antithyroid Drugs with IodineHSN N MeMMII 2IHISNHN N Me 3I S2N SMeMMI.I 2MMI-dicationMeNNHI 82-Isaia et al. J. Am. Chem. Soc. 2002, 124, 4538.J. Med. Chem. 2008, 51, 4050.HNSNHI 2IHINSNHOOPTUPTU.I 2Hadjiliadis et al. Eur. J. Inorg. Chem. 2003, 1635.Humboldt Kolleg, IIA Bangalore, February 2-5, 2011

Se-MMI – Tautomeric StructuresHNEN(1a) E = S(2a) E = SeMeNEHNMe(1b) E = S(2b) E = SeHNSeE = O, does not exist; E = Te, very unstable13-C NMR:1JSe-C= 220 HzNMe- 4.8 ppmC-Se single bond, 1 J se-c~ 110-140 Hz; C=Se double bond, 1 Jse-c ~ 220-240 Hz1.848 ÅRoy, Nethaji & Mugesh, J. Am. Chem. Soc. 2004, 126, 2712.Roy & Mugesh, J. Am. Chem. Soc. 2005, 127, 15207.Roy, Das & Mugesh, Inorg. Chim. Acta. 2007, 360, 303.Humboldt Kolleg, IIA Bangalore, February 2-5, 2011

Interactions of Antithyroid Drugs with IodineMeNNHSeSeI 3NNMeMeNNHSe2ISeHNNMeHumboldt Kolleg, IIA Bangalore, February 2-5, 2011Roy, Nethaji, & Mugesh, Org. Biomol. Chem., 2006, 4, 2883.

Hydrolysis by Metallo-β-LactamasesSOHNOCephalothinHNOSONaOOmβlSHNO ONOHSCO 2 HOHSHNO OHNOHSCO 2 HOHOHOHNOHNOSCefamandoleHONaOOHOSOMoxalactamMeNNN NOHN OMeHNONNNONaNSOHNOMeNNN NHumboldt Kolleg, IIA Bangalore, February 2-5, 2011OHNOSOHCefazolinmβlSSHN NSHON N MeN N MTTCH 3HONaONaOOOMeHN O HONOOMoxalactamOOOHN OMeHNOHOOONaONaSMeNNN N

Tautomeric Forms of MTT and MDTSHSThyroid GlandAnti-thyroid drugsN NCH 3N NSHN SNCH 3HHN NCH 3N NMTTSNNMDTSCH 3H 3 C N NMMISHO 2 C TPONH 2HOI - /H 2O 2TyrosineHIHOI OIICO 2 HThyroxine (T4)NH 2OHLPOH 2 O 2 , IOHI+IOHINH 2CO 2 HL-tyrosineNH 2CO 2 H3-iodo-L-tyrosineNH 2CO 2 H3,5-diiodo-L-tyrosineRoy, G.; Mugesh. G. J. Am. Chem. Soc. 2005, 127, 15207.Roy, G.; Nethaji, M.; Mugesh, G. J. Am. Chem. Soc. 2004, 126, 2712.Bhuyan, B. J.; Mugesh, G. Inorg. Chem. 2008, 47, 6569.Humboldt Kolleg, IIA Bangalore, February 2-5, 2011

Inhibition of LPO-catalyzed IodinationOHLPOH 2 O 2 , IOHI+IOHINH 2CO 2 HL-tyrosineNH 2CO 2 H3-iodo-L-tyrosineNH 2CO 2 H3,5-diiodo-L-tyrosineTamilselvi & Mugesh, ChemMedChem, 2009, 4, 512.No Compound Structure IC 50values (μM)H1 MMI N N4.09 ± 0.56HSSN NN NCH 32 MTT 7.29 ± 0.77SHN SCH 33 MDT N3.04 ± 0.65CH 3Humboldt Kolleg, IIA Bangalore, February 2-5, 2011

Sulfur-Iodine InteractionsNNNHNNNSSOHNONOSOHSSNNmβlCH 3NNSHNNNSNOOHNNOHOSOHCH 3CH 3HNNSISMeII 2IIIIIIMeSSNNHSI 2Tamilselvi, A.; Mugesh, G.HN NSMeHNNMeSSHISNNSMeI 5Bioorg. Med. Chem. Lett. 2010, 20, 3692.Humboldt Kolleg, IIA Bangalore, February 2-5, 2011

Sulfur-Iodine InteractionsHSNNSMeHONSONNMeHMDTMTDT240Raman Shift (cm -1 )20016012080(a)(b)(c)(d)(e)400.2 0.4 0.6 0.8 1.0 1.2I-I Bond Order(f)Thione-Iodine complexes (a) DMETT.I 2(b) MMI.I 2, (c) MDT.I 2, (d) PTU-I 2(e) MTDT-I 2, (f) free iodineTamilselvi, A.; Mugesh, G.Bioorg. Med. Chem. Lett. 2010, 20, 3692.Humboldt Kolleg, IIA Bangalore, February 2-5, 2011

Thyroid hormone binding in Transthyretin (TTR)Halogen binding sites P1, P2, P3 and their symmetry related pairs P1', P2', P3' in thyroidhormone transport protein Transthyretin. T 4(ball and stick - red) binding is greatly influenced by charged residues Lys15 andGlu54 in P1 pocket.Humboldt Kolleg, IIA Bangalore, February 2-5, 2011

Halogen bonding in human TTR-T4 complex Hydrogen bonding with Lys15 and Glu54 4-phenolic hydroxyl group forms watermediated hydrogen bond to Ser117.Acta Cryst. 1996, D52, 758-765.Halogen Bonding 5'-I atom of phenolic ring interacts with Leu110 backbone N atom in P3 pocket(I…..N, 3.5 Å) 3’- I atom interacts with the carbonyl oxygen of Ala109 in P2 pocket formed by othermonomer of the protein (I…..O, 2.8 - 3.3 Å)Humboldt Kolleg, IIA Bangalore, February 2-5, 2011

Binding of T3 with TTRJ. Biol. Chem. 2004, 279, 25, 26411 - 26416.Humboldt Kolleg, IIA Bangalore, February 2-5, 2011

Binding of 3,3’-T2 with human TTRSuperimposed structure of T4 (thick line)and T3 (light line) bound to human TTR.Amino acids are represented by singleletter codes.J. Biol. Chem. 1992, 267, 1, 353-357. 3'-I interacts directly with Ser117 side chain hydroxyl (I….O, 2.86 Å) although aseries of contacts with 108-110 and 117- 119 residues are possible with distancesbetween 2.86 Å & 3.72 Å)Humboldt Kolleg, IIA Bangalore, February 2-5, 2011

Binding of Thyroid Hormones to TTRIAffinityT4T2HOHOIIOOIHCO 2 HNH 2100 %T3HOOI Iactive hormoneIHCO 2 HNH 2IIH CO 2 HNH 20.07 %rT3HOIOT1HOIOHCO 2 H0.01%IIHCO 2 HNH 2NH 2The binding affinity decreases upon removal of iodines.Humboldt Kolleg, IIA Bangalore, February 2-5, 2011J. Biol. Chem. 1992, 267, 1, 353-357.

ID-3ID-1Iodothyronine DeiodinasesThe entire body metabolism depends on the amount of thyroid hormones produced.INACTIVATIONHOIOHOouter ringIIIT4Oinner ringIHCO 2 HNH 2ID-1ID-2ACTIVATIONproduces the activethyroid hormoneIIrT3HCO 2 HNH 2HOIIT3OIHCO 2 HHOONH 2ID-1ID-2IIT2HCO 2 HNH 2ID-3INACTIVATIONprotects tissues from anexcess of thyroid hormone.Behne et al. BBRC, 1990, 173, 1143; Berry et al. Nature 1991, 349, 438.Humboldt Kolleg, IIA Bangalore, February 2-5, 2011

Iodothyronine Deiodinase MimicsRRRSeHR = 2,6-diisopropylphenylRHOIIIOIHCO 2 Me(BpqSeH)NEt 3 , CDCl 350 o C, 7 daysHOHIIOIHCO 2 MeNHCOPr n65 %NHCOPr nGoto et al. Angew. Chem. Int. Ed. 2010, 49, 545.IOMeIBpqSeH, NEt 3CDCl 3 , 50 o C, 5 daysno deiodinationIOPhOHIIR'SeHOIH-RSeIIOH Enol-keto tautomerism is required Outer ring iodines are more reactiveRHumboldt Kolleg, IIA Bangalore, February 2-5, 2011RRthan the inner-ring ones

Iodothyronine Deiodinase MimicsIIHOOIHOOHIIT4H CO 2 HNH 2Inner-ringphosphate bufferpH 7.5, 37 o CSH SeHI IH CO 2 HrT3NH 2DeiodinationHOOIHOOHIIT3HCO 2 Hphosphate bufferpH 7.5, 37 o CIIT2HCO 2 HNH 2NH 2 Physiologically relevant conditions Highly specific to inner-ring deiodination Quantitative conversion of T4to rT3 in 30 hManna and Mugesh, Angew. Chem. Int. Ed. 2010, 49, 9246 - 9249.Humboldt Kolleg, IIA Bangalore, February 2-5, 2011

Picture 13Iodothyronine Deiodinase Mimics1003.5Relative Activity80604020T4rT3T3T2rate (µM/min)3.02.52.01.51.001231Compound230.54 6 8 10 12pHSeH SHSH SH SH SeH NHSHSePhNSeH1 2 34 5The rate of deiodination is highly pH dependent.A thiol adjacent to selenol is important for thedeiodination.Replacing -SeH with -SH reduces the activity.Humboldt Kolleg, IIA Bangalore, February 2-5, 2011

Possible MechanismIOPossible mechanismI(T4)SH...SeH- rT3SH Se I- HISSe Positive charge on inner–ring iodine decreases upon deiodination of T4. Halogen bonding may play an important role in the inner-ring deiodination.Humboldt Kolleg, IIA Bangalore, February 2-5, 2011

Iodothyronine Deiodinase MimicsSH SH SH SeH SeH SeH3 2 5141SH SH NHSHSeH NHSeH SeH NH918 9 10Se SH Se SeH11.6121.6066 7Does an increase in reactivity change the selectivity??Manna and Mugesh, Unpublished results.Humboldt Kolleg, IIA Bangalore, February 2-5, 2011

Iodothyronine Deiodinase MimicsSeH SeHSeH SeH NHrT3rT3T4T4T2T2 An increase in the reactivity does not change the selectivity, but it leadsto further deiodination. rT3 undergoes a further deiodination to form T2.Manna and Mugesh, Unpublished results.Humboldt Kolleg, IIA Bangalore, February 2-5, 2011

Iodothyronine Deiodinase MimicsSeHSeHHSeSeH SeHID-3ID-1IHOOouter ringIHOOI IT4inner ringIH CO 2 HNH 2HSeID-1ID-2IIrT3HCO 2 HNH 2HOIOIT3IHCO 2 HHOONH 2SeHID-1ID-2IIT2HCO 2 HNH 2ID-3SeH SeHHSeManna and Mugesh, Unpublished results.Humboldt Kolleg, IIA Bangalore, February 2-5, 2011

Effect of Se…N interactions on 77 Se NMRSeSeSe Se ... NH MeSe Se... N MeHumboldt Kolleg, IIA Bangalore, February 2-5, 2011

DFT CalculationsSe Se... N RSe Se ... NH R1, R = Me2, R = Et3, R = nPr4, R = iPr5, R = Me6, R = Et7, R = nPr8, R = iPr2AIM image of 1Compound r Se1··Se2/(Å) r Se2··N/(Å)

DFT CalculationsSe S..... N RSe S..... NH R9, R = Me10, R = Et11, R = nPr12, R = iPr13, R = Me14, R = Et15, R = nPr16, R = iPr10AIM image of 9Compound r Se··S/(Å) r S··N/(Å)

DFT CalculationsS Se.... N RS Se.... NH R17, R = Me18, R = Et19, R = nPr20, R = iPr21, R = Me22, R = Et23, R = nPr24, R = iPr18AIM image of 17Compound r S··Se/(Å) r Se··N/(Å)

AcknowledgementDepartment of Science and Technology (DST), New DelhiAlexander von Humboldt Foundation, GermanyGouriprasanna RoyDebasis DasA. TamilselviDebasish MannaThankYouHumboldt Kolleg, IIA Bangalore, February 2-5, 2011

Interactions of Antithyroid Drugs with IodineFar-IR spectra1.0MSeI141: ν(I-I) stretching vibration mode.Di-iodine vapor gives a strong band at 216, which0.8MSeI.I2Iappears at 180 in the solid state.277 274This band shifts to lower wavenumbers upon0.6141coordination to a donor atom, reflecting a reduction inthe I-I bond order.300 250 200 150 100ν - (cm-1)Roy, Nethaji, & Mugesh, Org. Biomol. Chem., 2006, 4, 2883.FT-Raman spectra I 3 - can exist as a real I 3 - entity or an I - ·I 2 adduct.110 : normally attributed to the symmetric stretching ofI 3 - – symmetric ion – one Raman active band.143 : the anti-symmetric stretching may becomeRaman active.Humboldt Kolleg, IIA Bangalore, February 2-5, 2011