2004-03-7Relevant academic research and scientific papers
IMIDAZOTETRAZINE COMPOUNDS
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Page/Page column 39; 42, (2020/03/02)
New synthetic methods to provide access to previously unexplored functionality at the C8 position of imidazotetrazines. Through synthesis and evaluation of a suite of compounds with a range of aqueous stabilities (from 0.5 to 40 hours), a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent was derived. Promising compounds were identified that possess activity against a panel of GBM cell lines, appropriate hydrolytic and metabolic stability, and brain-to-serum ratios dramatically elevated relative to TMZ, leading to lower hematological toxicity profiles and superior activity to TMZ in a mouse model of GBM.
Improved synthesis of β-D-6-methylpurine riboside and antitumor effects of the β-D- and α-D-anomers
Marasco Jr., Canio J.,Pera, Paula J.,Spiess, Arthur J.,Bernacki, Ralph,Sufrin, Janice R.
, p. 1015 - 1020 (2007/10/03)
6-Methylpurine-β-D-riboside (β-D-MPR) has been synthesized by coupling 6-methylpurine and 1-O-acety1-2,3,5-tri-O-benzoyl-D-ribose using conditions that produce the β-D-anomer exclusively. The in vitro antitumor effects of β-D-MPR and 6-methyl-purine-α-D-riboside (α-D-MPR) in five human tumor cell lines showed that β-D-MPR was highly active (IC50 values ranging from 6 to 34 nM). a-D-MPR, although less active than β-D-MPR, also exhibited significant antitumor effects (IC50 values ranging from 1.47 to 4.83 μM).
Convenient syntheses of 6-methylpurine and related nucleosides
Hassan,Abou-Elkair,Montgomery,Secrist III
, p. 1123 - 1134 (2007/10/03)
Efficient methods for the synthesis of 6-methylpurine (3), 9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-methylpurine (8), and 6-methyl-9-β-D-ribofuranosylpurine (5) are described. Methodology involving the (Ph3P)4Pd catalyzed cross-coupling reaction of CH3ZnBr with several different 6-chloropurine derivatives is described in high yield. This methodology now provides a facile and high-yielding synthesis of 8, which is needed in significant amounts for studies in cancer gene therapy.
Gene therapy of cancer: activation of nucleoside prodrugs with e. colipurine nucleoside phosphorylase
Secrist III, John A.
, p. 745 - 757 (2007/10/03)
During the last few years, many gene therapy strategies have been developed for various disease targets. The development of anticancer gene therapy strategies to selectively generate cytotoxic nucleoside or nucleotide analogs is an attractive goal. One such approach involves the delivery of herpes simplex virus thymidine kinase followed by the acyclic nucleoside analog ganciclovir. We have developed another gene therapy methodology for the treatment of cancer that has several significant attributes. Specifically, our approach involves the delivery of E. coli purine nucleoside phosphorylase, followed by treatment with a relatively non-toxic nucleoside prodrug that is cleaved by the enzyme to a toxic compound. .This presentation describes the concept, details our search for suitable prodrugs, and summarizes the current biological data. Copyright
DEAMINATION, INVOLVING RING OPENING, IN REACTIONS OF 1-AMINOPURINIUM MESITYLENESULFONATES WITH METHANOLIC AMMONIA
Kos, N. J.,Jongejan, H.,van der Plas, H. C.
, p. 4841 - 4848 (2007/10/02)
On reaction of 1-aminopurinium mesitylenesulfonates with methanolic ammonia N-deamination occurs.For 1-amino-, 1-amino-8-(methylthio)-, 1-amino-8-phenyl-, 1-amino-2-methyl-, 1-amino-6-methyl- and 1-amino-8-phenyl-9-methylpurinium mesitylenesulfonate this reaction proceeds for at least 75percent via ring opening as shown by the isolation of 1-15N-labelled purines when 15N-labelled methanolic ammonia was used. 1-Amino-9-methylpurinium mesitylenesulfonate gave N-deamination without ring opening.The reaction of 1-amino-6-(methylthio)purinium mesitylenesulfonate with methanolic ammonia involves, besides deamination, partial substitution of the methylthio group; no ring opening is involved.However, ring opening followed by substitution occurs in the reaction of 1-amino-2-(methylthio)purinium mesitylenesulfonate; the reaction proceeds via an adduct at position 2.
ACIDIC HYDROLYSIS OF 6-SUBSTITUTED 9-(2-DEOXY-β-D-ERYTHRO-PENTOFURANOSYL)PURINES AND THEIR 9-(1-ALKOXYETHYL) COUNTERPARTS: KINETICS AND MECHANISM.
Oivanen, Mikko,Loennberg, Harri,Zhou, Xiao-xiong,Chattopadhyaya, Jyoti
, p. 1133 - 1140 (2007/10/02)
The rate constants for the hydrolysis of several 6-substituted 9-(2-deoxy-β-D-erythro-pentofuranosyl)purines and 9-(1-alkoxyethyl)purines have been measured at different concentrations of oxonium ion.The effects that varying the polar nature of the alkoxy group exerts on the hydrolysis of unsubstituted 9-(1-alkoxyethyl)purines are interpreted to indicate that the reaction proceeds by a rate-limiting departure of the protonated base moiety with a concomitant formation of an alkoxyethyl oxocarbenium ion.The same mechanism is applied to the hydrolysis of 9-(2-deoxy-β-D-erythro-pentofuranosyl)purines by comparing the influences that 6-substituents have on the reactivity of these compounds and their 9-(1-alkoxyethyl) counterparts.No sign of anomerisation was detected, when the hydrolysis of 2'-deoxyadenosine was followed by 1H NMR spectroscopy.
Mechanisms for the Solvolytic Decompositions of Nucleoside Analogues. IX. Pathways for the Alkyline Hydrolysis of 6-Substituted 9-(1-Ethoxyethyl)purines
Loennberg, Harri,Lehikoinen, Pertti,Neuvonen, Kari
, p. 707 - 712 (2007/10/02)
A few 6-substituted 9-(1-ethoxyethyl)purines have been prepared and the rates of their base-catalyzed hydrolysis were measured by UV spectroscopy.The product mixtures were fractionated by preparative TLC and characterized by NMR and UV spectroscopy.The results obtained suggest that the alkaline cleavage of 9-(1-ethoxyethyl)purines generally proceeds by nucleophilic attack of hydroxide ion on C8 of the purine moiety, resulting in formation of appropriate 4,5-diaminopyrimidine and 8-methylpurine as final products.With 6-methoxy, 6-methylthio, and 6-chloro derivatives nucleophilic attack of hydroxide ion of C6 giving 9-(1-ethoxyethyl)hypoxanthine competes with this reaction.
Occurrence of the SNANRORC Mechanism in the Amination of 2-Substituted Purines with Potassium Amide in Liquid Ammonia
Kos, Nico J.,Plas, Henk C. van der
, p. 2942 - 2945 (2007/10/02)
The reactions of 2-chloro-, 2-fluoro- and 2-(methylthio)purine with potassium amide in liquid ammonia lead to the formation of 2-aminopurine.When these reactions are carried out with 15N-labeled potassium amide, ring-labeled 2-aminopurine is found.This demonstrates that a ring opening occurs during the amination.Formation of an anionic ? adduct at position 6 is proven by low-temperature NMR spectroscopy, and evidence is obtained for the formation of an open-chain intermediate, although this intermediate could not be isolated in a pure state.Reaction of the open-chain intermediate with hydriodic acid gives the thus far unknown 2-iodopurine. 2-Chloro-6-phenylpurine also reacts via ring opening into 2-amino-6-phenylpurine.However, 2-chloro-6-methyl- and 2-chloro-6,8-di-tert-butylpurine are found to be unreactive.
