Iodo Groups Research Articles

DNA Binding Compounds. VI. Synthesis and Characterization of 2,5'-Disubstituted Bibenzimidazoles Related to the DNA Minor Groove Binder Hoechst-33258

A series of compounds have been synthesized in which the basic 2-phenylbibenzimidazole structure of Hoechst 33258 has been modified to include various combinations of bromo, iodo, methoxy, amino, alkylamino and nitro groups in the terminal phenyl ring. Both sequential and convergent synthetic routes have been followed using coupling reactions of both imino ethers and aldehydes to 1,2-diamines. All these compounds were characterized by a combination of f.a.b . Mass spectrometry and 1H and 13C n.m.r. spectroscopy including inverse detection of long-range heteronuclear CH correlations (HMBC).

Building-block synthesis of porphyrin light-harvesting arrays

Photosynthetic organisms employ light-harvesting complexes to capture dilute sunlight and funnel energy to the reaction centers. Light-harvesting complexes are remarkable in achieving efficient energy migration among hundreds of pigments with avoidance of non-energy transfer quenching processes. In this communication we report a convergent strategy for preparing rigid, soluble arrays of covalently-linked porphyrins in various metalation states. The strategy employs readily available tetraarylporphyrins as modular building blocks. The porphyrins bear peripheral iodo or ethynyl groups and are facially-encumbered to suppress aggregation. The free base or metalloporphyrins are then joined via homogeneous Pd-mediated coupling reactions under basic conditions to give a desired assembly. We believe that this building-block approach provides an ideal route to model light-harvesting compounds. 10 refs., 1 fig.

Nickel boride reduction of aryl nitro compounds

Nickel boride smoothly reduces aryl nitro compounds to the corresponding anilines in the presence of iodo and ortho carboalkoxy groups in contrast to the problematic reductions by other methods.

Synthesis and characterization of halogeno- and pseudo-halogeno-thallium(III) porphyrin complexes. Variation of the co-ordination geometry as a function of the axial ligand

Several thallium(III) porphyrin complexes [Tl(por)X] with the axial ligand x = MeCO2, CF3CO2, Cl, Br, l, CN, SCN or N3, have been obtained via ligand-exchange reactions from the corresponding thallium(III) trifluoroacetates. All compounds were characterized by 1H NMR, UV/VIS spectroscopy, and elemental analysis. Fourteen compounds were investigated in detail by X-ray crystallography to obtain information on the influence of the axial ligand on the macrocycle core conformation in main-group metalloporphyrins and to establish the molecular stereochemistry of thallium(III) porphyrins with cyano, acetato, thiocyanato, bromo, iodo and azido groups as axial ligands.

A new convenient route for the synthesis of 4(5)‐(ω‐aminoalkyl)‐1 H‐imidazoles

AbstractA new route for the synthesis of 4(5)‐(ω‐aminoalkyl)‐1 H‐imidazoles 1 on a preparative scale through C5 lithiation of a 1,2‐diprotected imidazole is described. When the described 1,2‐diprotected 5‐lithio‐imidazole is treated with a 1‐chloro‐ω‐iodoalkane 5, selective substitution of the iodo group takes place. The chloro group of the resultant 1.2‐diprotected 5‐(ω chloroalkyl)imidazole can be easily converted into an amino group, but obviously other functional groups can be introduced as well. Subsequent deprotection of the 5‐substituted imidazole affords 4(5)‐(ω‐aminoalkyl)‐1 H‐imidazoles 1, as precursors for a large range of histaminergic compounds, in good overall yields.

Synthesis of telechelic 1,4-polybutadiene by metathesis reactions and borane monomers

A novel method for preparing telechelic 1,4-polybutadiene polymers which have functional groups, such as hydroxy and iodo groups, located at both ends of the polymer chains was described . The chemistry is based on borane-terminated 1,4-polybutadiene intermediates, in which the borane groups can be quantitatively converted to other functional groups under mild reaction conditions. The preparation of borane-terminated 1,4-polybutadiene involves two metathesis reactions which are very effective in providing telechelic polymers with not only a high degree of functionalization but also controllable molecular weight

Cationic and radical graft copolymerization of styrene onto iodochitin

In the presence of Lewis acids, cationic species were formed from iodochitin at the carbons bearing an iodo group, and graft copolymerization of styrene proceeded efficiently in nitrobenzene or somewhat less efficiently in nitromethane. As a catalyst, SnCl 4 was superior to TiCl 4 . Grafting percentages were as high as 800% under appropriate conditions. On irradiation by an excimer laser, the C-I bonds of iodochitin were cleaved to free radicals which initiated styrene grafting with low grafting yields but formation of very little homopolystyrene

Synthesis and anti-HIV activity of 4'-azido- and 4'-methoxynucleosides.

A series of nucleosides were synthesized in which the 4'-hydrogen was substituted with either an azido or a methoxy group. The key steps in the syntheses of the 4'-azido analogues were the stereo- and regioselective addition of iodine azide to a 4'-unsaturated nucleoside precursor followed by an oxidatively assisted displacement of the 5'-iodo group. The 4'-methoxynucleosides were made via epoxidation of 4'-unsaturated nucleosides with in suit epoxide opening by methanol. Reaction-mechanism considerations, empirical conformation rules, NMR-based conformational calculations, and NOE experiments suggest that the 4'-azidonucleosides prefer a 3'-endo (N-type) conformation of the furanose moiety. When evaluated for their inhibitory effect on HIV in A3.01 cell culture, all the 4'-azido-2'-deoxy-beta-D-nucleosides exhibited potent activity. IC50's ranged from 0.80 microM for 4'-azido-2'-deoxyuridine (6c) to 0.003 microM for 4'-azido-2'-deoxyguanosine (6e). Cytotoxicity was detected at 50-1500 times the IC50's in this series. The 4'-methoxy-2'-deoxy-beta-D-nucleosides were 2-3 orders of magnitude less active and less toxic than their azido counterparts. Modifications at the 2'- or 3'-position of the 4'-substituted-2'-deoxynucleosides tended to diminish activity. Further evaluation of 4'-azidothymidine (6a) in H9, PBL, and MT-2 cells infected with HIV demonstrated a similar inhibitory profile to that of AZT. However, 4'-azidothymidine (6a) retained its activity against HIV mutants which were resistant to AZT.

Toward the development of radiolabeled fluorophenyl azide-based photolabeling reagents: synthesis and photolysis of iodinated 4-azidoperfluorobenzoates and 4-azido-3,5,6-trifluorobenzoates

Two approaches for the incorporation of iodine into functionalized perfluorophenyl azides (PFPAs) were demonstrated by the synthesis of 3, 5, and 8, with the azido and iodo groups in the same aryl ring, and 14 15, with the azido and iodo groups in different aryl rings. These compounds opened the way for the incorporation of radioactive iodine into PFPAs and for their attachment to other molecules as photolabels

Direct Stereospecific Conversion of Acyclic Vicinal Diols into Olefins and Its Reaction Mechanism

A direct stereospecific conversion of acyclic vicinal diols into olefins was developed, and a study on the reaction mechanism elucidated that the reaction was s-cis with respect to the hydroxy groups and s- trans with respect to the iodo and hydroxy groups of the intermediate iodo alcohols.

125I]5-Iodo-6-nitro-2-piperazinylquinoline: a potent and selective ligand for the serotonin uptake complex

Two novel ligands with 4′ substitution on the Phenyl Ring B of biphenylthiol, 5-chloro-2-(2′-((dimethylamino)methyl)-4′-iodophenylthio)benzenamine (7) and 2-(2′-((dimethylamino)methyl)-4′-methoxyphenylthio)-5-iodobenzenamine (8), were prepared and tested as potential serotonin transporter (SERT) imaging agents. The new ligands displayed extremely high binding affinities to SERT (Ki=0.22±0.09 and 0.11±0.04 nM, respectively), with very low binding affinities to dopamine and norepinephrine transporters (Ki>1000 nM). The corresponding [125I]7 and [125I]8 were successfully prepared from tri-n-butyltin derivatives. They showed good brain uptakes and prolonged retention after intravenous injection in rats (brain uptake was 1.77% and 0.98% dose/g for [125I]7, and 0.92% and 0.29% dose/g for [125I]8, at 2 and 120 min, respectively). Significantly, [125I]7 showed excellent uptake and prolonged retention in the hypothalamus, where SERT concentration was highest. The hypothalamus/cerebellum (HY/CB) ratios (target/background ratios) were 4.24, 7.10, 8.24 and 12.6 at 2, 4, 6 and 12 h, respectively. The HY/CB ratios for [125I]8 were 3.97, 5.57 and 5.06 at 1, 2 and 4 h, respectively. Adding the 4′-iodo group to the Phenyl Ring B of Compound (7) appeared to reduce the rate of clearance from the brain, and kinetics favored uptake and retention in the hypothalamus. The localization of [125I]7 in the hypothalamus region in the rat brain could be blocked by pretreatment with (+)McN5652, escitalopram and ADAM (2), which are all selective SERT ligands (at 2 mg/kg iv, 5 min pretreatment). Ex vivo autoradiograms of rat brain sections (at 4 h after intravenous injection of [125I]7) showed intense labeling in regions of the brain known to have high SERT density. The excellent selective uptake and retention in the hypothalamus region suggest that [123I]7 is a potential lead compound for developing new imaging agents targeting SERT-binding sites with single-photon emission computed tomography.

Synthesis of fluorinated diisocyanates

Fluorinated diisocyanates of the general structure OCN(CH 2 ) 2 (CF 2 ) n (CH 2 ) 2 NCO were prepared from α,ω-diiodoperfluoroalkanes by insertion of ethylene into the CF 2 -I bond, displacement of the iodo groups with azide, reduction of the resulting azide groups to amines, and phosgenation of the diamine

New steroid haptens for radioimmunoassay: Synthesis of steroids substituted with thioether or ester linkages at the 2α-position

Haptens with bridge at the 2-position have not yet heen explored. Radioimmunoassays with antibodies directed against 2α-alkyl bridged steroid haptens are expected to he highly specific due to greater topographical exposure and similarity in conformation to the native steroid. The 2α-alkyl bridged haptens were synthesized by first adding a cyclopropane ring to 2-methylene-4-en-3-one. Selective opening of the three-membered ring with trimethyl silyl iodide and transformation of the iodo group gave a carbocyclic acid, the desired analog for conjugation with protein.

Chemical modifications and amino acid substitutions in recombinant hirudin that increase hirudin-thrombin affinity

Recombinant hirudin (r-hirudin), unlike the naturally occurring leech protein, lacks a sulfate ester on Tyr-63 which reduces its binding affinity to thrombin by 3-10-fold. We demonstrate that nitration or iodination of Tyr-63 restores hirudin-thrombin affinity to levels similar to or exceeding that of the natural inhibitor. In contrast, nitration of Tyr-3 reduces the affinity of hirudin for thrombin. These chemical modifications results in multiple reaction products that are readily separated by reverse-phase HPLC. The mechanism of the observed changes in thrombin affinity may involve a reduction in the pK of the hydroxyl group of tyrosine due to substitution of the electrophilic iodo or nitro group on the phenyl ring, resulting in an increased negative charge at neutral pH. For Tyr-63, this effect mimics the sulfatotyrosine of natural hirudin, leading to an increased thrombin affinity at the anion-binding exosite. For Tyr-3, the increased polarity may destabilize its interaction within the apolar-binding site of thrombin. Substitution of the highly conserved Tyr-3 residue with Phe or Trp not only enables specific and quantitative chemical modification at Tyr-63 but also independently increases hirudin-thrombin affinity. Kinetic analysis of thrombin inhibition showed that enhanced binding by r-hirudin(nitro-Tyr-63) is due to an increase in the association rate between hirudin and thrombin whereas the reduced binding of r-hirudin(nitro-Tyr-3) results from a large increase in the dissociation rate. These observations indicate that specific segments within both the amino- and carboxy-terminal regions of hirudin interact with thrombin.

Synthesis and isomerism of neutral and cationic dimethylplatinum(IV) complexes. Crystal structure of the bis(pyrazol-1-yl)(thien-2-yl)methane complex PtI 2Me 2{(pz) 2(thi)CH- N,N′}

The reaction of [PtMe 2(SEt 2)] 2 with tripodal nitrogen donor ligands and iodine in dichloromethane gives diiododimethylplatinum(IV) complexes, PtI 2Me 2{(pz) 2(L) CH- N,N′}, in which the N,N′-bidentate ligands are trans to the cis-PtMe 2 group and have one uncoordinated donor group. The bis(pyrazol-1-yl)(thien-2-yl)methane complex, PtI 2Me 2{(pz) 2(thi)CH- N,N′}, has PtI bond lengths of 2.6199(7) and 2.6649(6) Å for the trans-PtI 2 group, and PtC bond lengths of 2.070(7) and 2.097(9) Å, and PtN bond lengths of 2.181(5) and 2.192(6) Å. Complexes of (pz) 2(L)CH [L = N-methylimidazol-2-yl (mim), pyridin-2-yl (py)] exist as a mixture of isomers, with an isomer ratio as expected for a random distribution of coordinated pz and L donor groups, 2:1 for 2pz: (pz + L) coordination. The complexes of (pz) 3CH, (pz) 2(mim)CH, and (pz) 2(py)CH are converted into [PtIMe 2{(pz) 2(L)CH- N,N′,N″}]I on heating, and the cations of the unsymmetrical tridentate ligands (pz) 2(L)CH (L = py, mim) also exist as isomers. The isomers have the donor group L trans to a methyl or iodo group, where the ratio (L trans to Me):(L trans to I) is 2:1 for L = py (as expected for a random distribution of isomers) and 1:1 for L = mim.

Photoaffinity labeling and partial purification of the beta cell sulfonylurea receptor using a novel, biologically active glyburide analog.

An iodinated analog of the sulfonylurea, glyburide, has been synthesized which can be labeled to high specific activity and used to photolabel the sulfonylurea receptor. 5-Iodo-2-hydroxy-"glyburide", has an iodo group replacing the chlorine at position 5 and a methoxy residue replacing the hydroxy group at position 2 on the benzamido ring. This analog retains biologic activity stimulating insulin secretion from a hamster beta cell line (HIT cells) at the same ED50 (0.4 nM) as glyburide. Scatchard analysis demonstrated high and low affinity binding sites on HIT cell membranes (Kd values of 0.36 nM and 277 nM and Bmax values of 1.6 and 100 pmol/mg of membrane protein, respectively). Competitive binding assays with unlabeled glyburide or 5-iodo-2-hydroxyglyburide yield Ki values of 0.5 and 1.0 nM, respectively. The analog can be covalently linked by ultraviolet irradiation to a membrane protein of Mr = 140,000. The photolabeling is completely blocked by unlabeled glyburide or the analog. Two other species of Mr = 65,000 and 43,000 are also photolabeled; these may be the low affinity sites. After photolabeling, the receptor has been purified partially by chromatographic procedures and is suitable for obtaining peptide sequence. The 140,000 molecular weight protein is identified as the sulfonylurea receptor since its binding constant, 0.36 nM, is closely correlated with its ability to stimulate insulin secretion (ED50 congruent to 0.4 nM).

DNA sequence analysis of mutations induced by N-2-acetylamino-7-iodofluorene in plasmid pBR322 in Escherichia coli

The spectrum of mutations induced by N-2-acetylamino-7-iodofluorene (AAIF) was analyzed in a forward mutation system based on mutagenesis directed to a small restriction fragment in the tetracycline resistance gene of plasmid pBR322. AAIF was found to induce frameshift mutations and base-pair substitutions at approximately equal frequencies. The frameshift mutations were mostly deletions of single base-pairs, but -2 frameshifts and +1 frameshifts were also detected. With one exception, the substitutions were transversions initiated at a G.C base-pair. Both frameshift mutations and transversions occurred preferentially at sites of repetitive guanine residues. Although AAIF and the related aromatic amines N-2-acetylaminofluorene (AAF) and N-2-aminofluorene (AF) all bind to the C-8 position of guanine, they have different effects on DNA conformation, and these differences are reflected in their mutation spectra. Previous studies have provided evidence that AAF adducts can trigger a B to Z conformational change in alternating GC sequences or displacement of the guanine by the fluorene ring in other sequences; the principal result is two classes of frameshift mutations. AF, whose DNA interaction involves outside binding rather than insertion and denaturation, primarily induces base-pair substitutions. AAIF adducts are chemically similar to AAF adducts, but the iodo group apparently hinders insertion of the fluorene ring into DNA. Consistent with this model, the mutation spectrum of AAIF combines properties of the mutation spectra of both AAF and AF.

Functionalization of Cubanes and Homocubanes via Oxidative Displacement of Iodine Using Hypervalent Iodine

Abstract The iodo group in 4-iodo-1-carbomethoxycubane (1) can be replaced by mesyloxy, tosyloxy and chloro by oxidative displacement with C6H5I(OH)OMs, C6H5I(OH)OTs and C6H5ICl2, respectively. Similarly, the iodo group in the homocubyl compound 4-iodo-1-bromopentacyclo[4.3.0.02,5.03,8.04,7]nonane-9-one ethylene acetal (2) was analogously replaced by mesyloxy, tosyloxy and chloro. Possible pathways for these reactions are discussed.

Structure-activity relationships of pyrimidine nucleosides as antiviral agents for human immunodeficiency virus type 1 in peripheral blood mononuclear cells.

The structure-activity relationships of several pyrimidine nucleosides related to 3'-azido-3'-deoxythymidine (AZT) were determined in human immunodeficiency virus type 1 (HIV-1) infected human peripheral blood mononuclear cells. These studies indicated that nucleosides with a 3'-azido group on the sugar ring exhibited the most potent antiviral activity. Substitution at C-5 with H, CH3, and C2H5 produced derivatives with the highest potency, whereas alkyl functions greater than C2, including bromovinyl substitution reduced the antiviral potency significantly. Changing the 3'-azido function to an amino or iodo group reduced the antiviral activity. Replacement of the uracil ring by cytosine or 5-methylcytosine produced analogues with high potency and low toxicity. Modification of the 5'-hydroxy group markedly reduced the antiviral activity. Similarly, various C-nucleoside analogues related to AZT and 2',3'-dideoxycytidine were inactive and nontoxic. From these systematic studies 3'-azido-2',3'-dideoxyuridine (5a), 3'-azido-5-ethyl-2',3'-dideoxyuridine (5c), and 3'-azido-2',3'-dideoxycytidine (7a) and its 5-methyl analogue (7b) were identified as potent and selective anti-HIV-1 agent in primary human lymphocytes.

Hypolipidemic 2-[4-(1,1-dimethylethyl)phenyl]-4H-3,1-benzoxazin-4-ones. Structure-activity relationships of a novel series of high-density lipoprotein elevators.

The preparation and plasma lipid altering characteristics of a series of 4H-3,1-benzoxazin-4-ones are described. Hypocholesterolemic, hypotriglyceridemic, and high-density-lipoprotein elevating properties are found for derivatives bearing a 4-(1,1-dimethylethyl)phenyl group at the 2-position, and this activity is displayed in both hypercholesterolemic and in normolipidemic rats when the ring system is substituted at position 6 with hydrogen, methyl, chloro, or iodo groups, and is optimal when the 6-position is substituted by a bromine atom. Evidence is presented suggesting that a metabolite or degradation product is responsible for the changes in lipoprotein concentration observed with active molecules of this type. Synthesis of anticipated degradation products of the active molecules gave products displaying the expected in vivo activity, but no improvement in the narrow therapeutic margin of the best compound, 6-bromo-2-[4-(1,1-dimethylethyl)phenyl]-4H-3,1-benzoxazin-4-one, was obtained.