Boronated dipeptide borotrimethylglycylphenylalanine as a potential boron carrier in boron neutron capture therapy for malignant brain tumors.

Takagaki, M., Ono, K., Masunaga, S-I., Kinashi, Y., Oda, Y., Miyatake, S-I., Hashimoto, N., Powell, W., Sood, A. and Spielvogel, B. F. Boronated Dipeptide Borotrimethylglycylphenylalanine as a Potential Boron Carrier in Boron Neutron Capture Therapy for Malignant Brain Tumors. Radiat. Res. 156, 118-122 (2001).A boronated dipeptide, borotrimethylglycylphenylalanine (BGPA), was synthesized as a possible boron carrier for boron neutron capture therapy (BNCT) for malignant brain tumors. In vitro, at equal concentrations of (10)B in the extracellular medium, BGPA had the same effect in BNCT as p-boronophenylalanine (BPA). Boron analysis was carried out using prompt gamma-ray spectrometry and track-etch autoradiography. The tumor:blood and tumor:normal brain (10)B concentration ratios were 8.9 +/- 2.1 and 3.0 +/- 1.2, respectively, in rats bearing intracranial C6 gliosarcomas using alpha-particle track autoradiography. The IC(50), i.e. the dose capable of inhibiting the growth of C6 gliosarcoma cells by 50% after 3 days of incubation, was 5.9 x 10(-3) M BGPA, which is similar to that of 6.4 x 10(-3) M for BPA. The amide bond of BGPA is free from enzymatic attack, since it is protected from hydrolysis by the presence of a boron atom at the alpha-carbon position of glycine. These results suggest promise for the use of this agent for BNCT of malignant brain tumors. Further preclinical studies of BGPA are warranted, since BGPA has advantages over both BPA and BSH.

New boron analogues of pyrophosphates and deoxynucleoside boranophosphates.

Tetraethyldicyanoborane pyrophosphate (2) and 3'-(diethylphosphite-cyanoborano)-5'-dimethoxytrityl.N(4)-benzoyl-deoxycytidine (3) have been synthesized in 70% and 76% yields, respectively. The compatibility of the substituted boranophosphates with common protecting groups is hereby demonstrated.Boron containing biologically active compounds, such as nucleosides and nucleotides (1-6) and amino acids (7-9) are important due to their potential therapeutic activity, research and diagnostic applications. Many boron containing compounds have shown promising activity as anticancer, (10.) (11.) (12) antiinflammatory,(13) and antiosteoporotic (13)agents. Oligonucleotdes in which a non-bridging oxygen atom is replaced by a borane(BH(3)) group are a very important class of modified nucleic acids. (1.) (3.) (14-16) The BH(3) group is isoelectronic with oxygen in natural oligonucleotides and isoelectronic and isostructural with the oligonucleotide methyl phosphonates, which are nuclease resistant. On the other hand, the alpha-borano triphosphates are good substrates for DNA polymerases and incorporation of boranophosphates into DNA causes an increase in the resistance to exo- and endonucleases (2.) (17a) as compared to non-modified DNA. There are also notable applications of the alpha-borano triphosphates in PCR sequencing (17a) and nucleic acid detection (17b).

Reagents for bioorganic synthesis. 6. The design and synthesis of two novel polyfunctional organic reagents for biomacromolecular modification.

The design, synthesis, structure, and properties of two tetrafunctional organic reagents, namely, 2,2'-sulfonylbis[3-(carboxymethylamino)-(E,E)-N-(2-chloroeth yl)propenamide] (SBCCP) (1) and 2,2'-sulfonylbis[3-(carboxymethylamino)-(E,E)-N-(2-oxoeth yl)propenamide] (SBCOP) (2) are reported. Reagents 1 and 2 contain reactive bis(alkyl halide) and bis(aldehyde) functions, respectively, as well as bis(carboxylic acid) moieties. The reagents have potential applications for biomacromolecular cross-linking, in particular for the cross-linking of hemoglobin subunits. Single-crystal X-ray diffraction data of synthetic intermediates (4,5, and 12) provided information about structural features and tether lengths of the target reagents.

Structure of a potential cross-linking reagent: 2,2'-bis(methoxymethylene)-2,2'-sulfonyldiacetonitrile (MMSBA).

The title compound (I) was prepared as a potential cross-linking reagent for nucleic acids and/or proteins. The compound is a stable, but reactive, crystalline solid which can be stored indefinitely upon adequate protection. The reagent reacts with amine nucleophiles - primary, secondary as well as heterocyclic - to afford bis-enamines. C8H8N2O4S, Mr = 228.23, monoclinic, C2/c, a = 18.031 (5), b = 9.372 (3), c = 13.455 (6) A, beta = 108.08 (5) degrees, V = 2161 (1) A3, Z = 8, Dx = 1.40 g cm-3, lambda(Mo K alpha) = 0.71069 A, mu = 2.81 cm1, F(000) = 944, T = 295 K. Final R = 0.041 for 1033 observed reflections. The bond distances in (I) are: S-O, 1.424 (3); S-C, 1.737 (4); C-CN, 1.417 (5); C=C, 1.342 (5); = C(H)-O, 1.295 (4); and C identical to N, 1.138 (5) A. The diagonal distance, alpha-alpha', between the two trans C atoms is 4.976 A.