7-Azaindole. IV. The Hydrogenation of 7-Azaindole and Related Compounds<sup>1,2</sup>

Robison, Michael M.; Butler, Florence P.; Robison, Bonnie L.

doi:10.1021/ja01567a057

Cited by 19 publications

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“…In TPI (2), the iminopyrrolidine ring will be essentially fully protonated since the pK a of the protonated form of the close structural analogue 7-methyl-2,3,3a,4,5,6-hexahydro-7H-pyrrolo[2,3-b]pyridine is 11.5. 45 Overall therefore, TPI and the 5-halo-6-[(2′-aminoimidazol-1′-yl)methyl]uracils (3, X ) Cl, Br) are expected to be zwitterionic at pH 7.4. In contrast, since uracil has a pK a of 9.43 46 (with both N-H groups contributing to the observed value), the situation for 3, X ) H is more complex, all four species (zwitterionic, neutral, anionic and cationic) are likely to coexist in significant amounts (especially at 37 °C), and the estimation of their proportions is uncertain (even discounting ionization at 'uracil'-N3, four micro pK a values would be required); however, the proportion of the required zwitterion is likely to be small and binding to HPO 4 2and cationic Arg202 and Lys221 at the active site will be compromised (to save space, Arg202 and Lys221 are not shown in Scheme 1b).…”

Section: Resultsmentioning

confidence: 99%

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Aminoimidazolylmethyluracil Analogues as Potent Inhibitors of Thymidine Phosphorylase and Their Bioreductive Nitroimidazolyl Prodrugs

et al. 2004

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Thymidine phosphorylase (TP) is an important target enzyme for cancer chemotherapy because it is expressed at high levels in the hypoxic regions of many tumors and inhibitors of TP have been shown in animal model studies to inhibit angiogenesis and metastasis, and to promote tumor cell apoptosis. The 5-halo-6-[(2'-aminoimidazol-1'-yl)methyl]uracils (3, X = Cl, Br) are very potent inhibitors of E. coli and human TP with IC(50) values of approximately 20 nM when the enzyme concentration is approximately 40 nM. Their 4'-aminoimidazol-1'-yl analogues (4, X = Cl, Br) are >350-fold less active with IC(50) values of approximately 7 microM. The 5-unsubstituted analogues (3 and 4, X = H) were both less active than their 5-halo derivatives. Determination of pK(a) values and molecular modeling studies of these compounds in the active site of human TP was used to rationalize their activities. The finding that 3, X = Br has a poor pharmacokinetic (PK) profile in mice, coupled with the desire for tumor selectivity, led us to design prodrugs. The corresponding 2'-nitroimidazol-1'-ylmethyluracils (5, X = Cl, Br) are >1000-fold less active (IC(50) 22-24 microM) than their 2'-amino analogues and are reduced to the 2'-amino inhibitors (3, X = Cl, Br) by xanthine oxidase (XO). As XO is also highly expressed in many tumors, the 2'-nitro prodrugs have the potential to selectively deliver the potent 2'-aminoimidazol-1'-yl TP inhibitors into hypoxic solid tumors.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Aminoimidazolylmethyluracil Analogues as Potent Inhibitors of Thymidine Phosphorylase and Their Bioreductive Nitroimidazolyl Prodrugs

et al. 2004

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“…Although some 6,6- and 6,5-bicyclic amidines have been reported, − the syntheses are generally either tedious or are not easily modifiable to produce other amidine ligands with other substitution patterns. Regardless, in order to maximize precursor volatility, the lowest possible ligand molecular weight is generally desirable; moreover, a 5,5-bicyclic system would most effectively restrict β-hydrogen or β-methyl migration to the metal.…”

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Synthesis of 5,5-Bicyclic Amidines as Ligands for Thermally Stable Vapor Deposition Precursors

2017

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We describe the syntheses of three fully aliphatic 5,5-bicyclic amidines. The syntheses are facile and scalable and can be easily modified to produce other 5,5-bicyclic amidine ligands with other substitution patterns. Treatment of one of the ligands with KHMDS and subsequent transmetalation with CuCl resulted in a dimeric copper(I) bicyclic amidinate complex in 55% yield after recrystallization. This modestly air stable complex exhibits good volatility and thermal decomposition rates 1 order of magnitude lower than those of a similar, but acyclic, copper(I) amidinate. Together, the ligands enable a general method for producing a library of thermally stable metal amidinate precursors with a wide variety of metals for use in vapor deposition.

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“…The formation of quaternary salts was also reported by alkylation of 7-azaindole [20], 1-deazapurine [21], adenine [22,23], indolo [2,3-b]quinoxaline [24].…”

Section: Resultsmentioning

confidence: 85%

7-Substituted pyrrolo[2,3-d]pyrimidines for the synthesis of new 1-deazapyrimido[1,2,3-cd]purines

2017

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7-Azaindole. IV. The Hydrogenation of 7-Azaindole and Related Compounds^1,2

Cited by 19 publications

References 0 publications

Aminoimidazolylmethyluracil Analogues as Potent Inhibitors of Thymidine Phosphorylase and Their Bioreductive Nitroimidazolyl Prodrugs

Aminoimidazolylmethyluracil Analogues as Potent Inhibitors of Thymidine Phosphorylase and Their Bioreductive Nitroimidazolyl Prodrugs

Synthesis of 5,5-Bicyclic Amidines as Ligands for Thermally Stable Vapor Deposition Precursors

7-Substituted pyrrolo[2,3-d]pyrimidines for the synthesis of new 1-deazapyrimido[1,2,3-cd]purines

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7-Azaindole. IV. The Hydrogenation of 7-Azaindole and Related Compounds1,2

Cited by 19 publications

References 0 publications

Aminoimidazolylmethyluracil Analogues as Potent Inhibitors of Thymidine Phosphorylase and Their Bioreductive Nitroimidazolyl Prodrugs

Aminoimidazolylmethyluracil Analogues as Potent Inhibitors of Thymidine Phosphorylase and Their Bioreductive Nitroimidazolyl Prodrugs

Synthesis of 5,5-Bicyclic Amidines as Ligands for Thermally Stable Vapor Deposition Precursors

7-Substituted pyrrolo[2,3-d]pyrimidines for the synthesis of new 1-deazapyrimido[1,2,3-cd]purines

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7-Azaindole. IV. The Hydrogenation of 7-Azaindole and Related Compounds^1,2