Studies of pendant-arm macrocyclic ligands. Part 4. Two penta-aza macrocycles based on 1-(2′-dimethylaminoethyl)-1,5,9,13-tetra-azacyclohexadecane and its complexes with bivalent metal ions

Alcock, Nathaniel W.; Curzon, Eirian H.; Moore, Peter; Omar, Hadi A. A.

doi:10.1039/dt9850001361

Cited by 6 publications

(5 citation statements)

References 1 publication

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“…18 Clearly, the conformational requirements for formation of a pendant transition metal complex are (26). In full agreement with the literature, 14,29,30 the UV absorption spectrum of 26 (9.0 mM) in aqueous 1 M NaClO 4 (pH 6.9) gave three bands at 327 (sh), 531 (…”

Section: Resultssupporting

confidence: 90%

“…Addition of 1 equiv of Ni(II) perchlorate in n -butanol, which had been previously distilled to one-half volume to remove water, to an ethanol solution of 15 gave a bright purple precipitate which analyzed to the formula 15 :Ni(ClO 4 ) 2 ( 26 ). In full agreement with the literature, ,, the UV absorption spectrum of 26 (9.0 mM) in aqueous 1 M NaClO 4 (pH 6.9) gave three bands at 327 (sh), 531 (ε = 10) and 934 (ε = 9.1) nm, consistent with a 5-coordinate, high-spin Ni(II) complex in which the pyridine moiety is pendant-coordinated. Dissolving the solid 26 (9.0 mM) in 5 M aqueous perchloric acid gave an immediate color change from purple ( 26 ) to orange ( 27 ) (this concentration of HClO 4 was required for complete conversion of 26 to 27 ), which was found to be reversible upon alternate additions of sodium hydroxide and perchloric acid.…”

Section: Resultssupporting

confidence: 89%

“…In support of an alternate, transition metal-mediated anti-HIV inactivation mechanism for the proposed model, it was also necessary to demonstrate that formation of a pendant-coordinated transition metal complex is achievable for the pyridine analogs 8c,d. Interestingly, of the pyridylcyclam literature examples shown in Scheme 2, only 13 and 14 formed pendant-coordinated complexes with Ni(II), consistent with several other examples of 14-29 and 16-membered 30 tetraazamacrocyclic ligands featuring pendant amino or pyridine groups. The existence of a 5-coordinate, low-spin, d 7 Ni-(III) complex of 12 in which the pyridine group was axially coordinated was only observed in the ESR spectrum when the 12:Ni(II) complex was chemically oxidized.…”

Section: Resultssupporting

confidence: 83%

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Synthesis and Structure−Activity Relationships of Phenylenebis(methylene)- Linked Bis-tetraazamacrocycles That Inhibit Human Immunodeficiency Virus Replication. 2. Effect of Heteroaromatic Linkers on the Activity of Bicyclams

Padmanabhan

et al. 1996

J. Med. Chem.

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A series of bicyclam analogs connected through a heteroaromatic linker have been synthesized and evaluated for their inhibitory effects on HIV-1 (IIIB) and HIV-2 (ROD) replication in MT-4 cells. The activity of pyridine- and pyrazine-linked bicyclams was found to be highly dependent upon the substitution of the heteroaromatic linker connecting the cyclam rings. For example, 2,6- and 3,5-pyridine-linked bicyclams were potent inhibitors of HIV-1 and HIV-2 replication, whereas the 2,5- and 2,4-substituted pyridine-linked compounds exhibited substantially reduced activity and, in addition, were found to be highly toxic to MT-4 cells. We have subsequently discovered that these effects are not unique; amino-substituted linkers also have the potential to deactivate phenylenebis(methylene)-linked bicyclams. A model is proposed to explain the deactivating effects of the pyridine group in certain substitution patterns based on the ability of the pyridine nitrogen to participate in pendant conformations (complexation) with the adjacent azamacrocyclic ring, which may involve hydrogen bonding or coordination to a transition metal. The introduction of a sterically hindering group such as phenyl at the 6-position of the 2,4-substituted pyridine-linked bicyclam appears to prevent pendant conformations, providing an analog with comparable anti-HIV-1 and anti-HIV-2 activities to the parent m-phenylenebis(methylene)-linked bicyclam. The results of this study have been used to develop a quantitative structure-activity relationship model with improved predictive capability in order to aid the design of antiviral bis-azamacrocyclic analogs.

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Section: Resultssupporting

confidence: 90%

Section: Resultssupporting

confidence: 89%

Section: Resultssupporting

confidence: 83%

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Synthesis and Structure−Activity Relationships of Phenylenebis(methylene)- Linked Bis-tetraazamacrocycles That Inhibit Human Immunodeficiency Virus Replication. 2. Effect of Heteroaromatic Linkers on the Activity of Bicyclams

Padmanabhan

et al. 1996

J. Med. Chem.

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“…A modified Richman-Atkins22 cyclization of 5a with the disodium salt of 6a (prepared in situ, by reaction of 6a with NaH in DMF) gave the benzyl compound 7a, which was subjected to hydrogenolysis with Pd(OH)2 in refluxing formic acid giving 8a. In a similar manner, substituting dipropanolamine trimethanesulfonate (5b) 23 for Sa in the cyclization reaction and subsequent hydrogenolysis of 7b afforded the desired [ 161aneN4 macrocycle 8b. Alternatively, synthesis of the appropriately protected [13laneN4 (812) and [ 151aneN4 (8d) macrocycles was accomplished via the bis-methanesulfonates 5c and 5d in which a diethoxyphosphoryl (Dep) is targeted for the selective deprotection reaction.…”

Section: Chemistrymentioning

confidence: 98%

Synthesis and Structure-Activity Relationships of Phenylenebis(methylene)-Linked Bis-Tetraazamacrocycles That Inhibit HIV Replication. Effects of Macrocyclic Ring Size and Substituents on the Aromatic Linker

Bridger¹,

Skerlj²,

Thornton³

et al. 1995

J. Med. Chem.

211

183

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We have previously described the potent and selective inhibition of several strains of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) by JM2763, an n-propyl-linked dimer of the 1,4,8,11-tetraazamacrocyclic (cyclam) ring system. Upon further investigation, we have also found that incorporating an aromatic rather than aliphatic linker leads to analogs with higher antiviral potency. The prototype, JM3100 (19a, isolated as the octahydrochloride salt), which contains a p-phenylenebis(methylene) moiety linking the cyclam rings, inhibited the replication of HIV-1 (IIIB) and HIV-2 (ROD) at EC50's of 4.2 and 5.9 nM, respectively, while remaining nontoxic to MT-4 cells at concentrations exceeding 421 microM. In order to identify the structural features of bis-tetraazamacrocycles required for potent activity, we have prepared a novel series of phenylenebis(methylene)-linked analogs, in which the macrocyclic ring size was varied from 12 to 16 ring members. Depending upon the substitution of the phenylenebis(methylene) linker (para or meta), sub-micromolar anti-HIV activity was exhibited by analogs bearing macrocycles of 12-14 ring members but with varying cytotoxicity to MT-4 cells. Furthermore, while we found that identical macrocyclic rings are not required for activity, substituting an acyclic polyamine equivalent for one of the cyclam rings in 19a resulted in a substantial reduction in anti-HIV potency, clearly establishing the importance of the constrained macrocyclic structure. A short series of transition metal complexes of 19a were also prepared and evaluated. Complexes of low kinetic stability such as the bis-zinc complex retained activity comparable to that of the parent compound. Finally, the activity of bicyclam analogs appears to be insensitive to the electron-withdrawing or -donating properties of substituents introduced onto the linker, but sterically hindering groups such as phenyl markedly reduced activity. As a result, several analogs with anti-HIV potency comparable to that of 19a have been identified.

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“…38 The five-coordinate Cu11 compound of one di-7V-(carboxymethyl)-substituted pyridyl tetraazamacrocycle has three of the four ring nitrogen atoms and both carboxylato group oxygen atoms coordinated. 39 Coordination of the macrocycle nitrogens for these ligands with Ni11 is generally nonlabile, but the carboxylato groups are labile and in acid solution the carboxylato groups are rapidly and reversibly decoordinated and protonated. Similar behavior is shown by compounds of diam with Ni11, the secondary amine nitrogens of the macrocycle being nonlabile and the coordinated primary amine groups labile.…”

Section: T H I S C O N T E N T Imentioning

confidence: 99%

Compounds of iron(III) with trans-1,4,8,11-tetraazacyclotetradecane-6,13-dicarboxylic acid: structures of trans-(trans-1,4,8,11-tetraazacyclotetradecane-6,13-dicarboxylato)iron(III) perchlorate and trans-(trans-1,4,8,11-tetraazacyclotetradecane-6,13-dicarboxylato)iron(III) trans-(trans-1,4,8,11-tetraazacyclotetradecane-6,13-dicarboxylic acid) dichloroiron(III) trans-1,4,8,11-tetraazoniacyclotetradecane-6,13-dicarboxylic acid dichloride tetraperchlorate tetrahydrate

Curtis¹,

Li²,

Weatherburn³

1993

Inorg. Chem.

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Studies of pendant-arm macrocyclic ligands. Part 4. Two penta-aza macrocycles based on 1-(2′-dimethylaminoethyl)-1,5,9,13-tetra-azacyclohexadecane and its complexes with bivalent metal ions

Cited by 6 publications

References 1 publication

Synthesis and Structure−Activity Relationships of Phenylenebis(methylene)- Linked Bis-tetraazamacrocycles That Inhibit Human Immunodeficiency Virus Replication. 2. Effect of Heteroaromatic Linkers on the Activity of Bicyclams

Synthesis and Structure−Activity Relationships of Phenylenebis(methylene)- Linked Bis-tetraazamacrocycles That Inhibit Human Immunodeficiency Virus Replication. 2. Effect of Heteroaromatic Linkers on the Activity of Bicyclams

Synthesis and Structure-Activity Relationships of Phenylenebis(methylene)-Linked Bis-Tetraazamacrocycles That Inhibit HIV Replication. Effects of Macrocyclic Ring Size and Substituents on the Aromatic Linker

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