Iwona M. Wyzlic

A general, convenient way to carborane-containing amino acids for boron neutron capture therapy

Abstract A general convenient procedure for the synthesis of caborane-containing amino acids in good yield has been developed. The synthesis of o-carboranylalanine 1, O-(o-carboran-1-ylmethyl)-tyrosine 2 and p-(o-carboran-1-yl)-phenylalanine 3 is reported.

Strategies for the design and synthesis of boronated nucleic acid and protein components as potential delivery agents for neutron capture therapy

PURPOSE Strategies for the design and synthesis of boronated nucleosides, amino acids, and peptides as potential delivery agents for boron neutron capture therapy (BNCT) are described. METHODS AND MATERIALS For BNCT to be a useful treatment modality, there is a need to design and synthesize nontoxic boron compounds that selectively target tumor cells, accumulate in sufficient amounts (20-30 micrograms 10B/g of tumor) and persist at therapeutic levels for a sufficient time prior to neutron irradiation. Boronated nucleosides, amino acids and peptides are such promising target compounds. Such structures may be selectively used by proliferating neoplastic cells compared with mitotically less active normal cells and therefore achieve the tissue differentials necessary for BNCT. RESULTS The rationale for synthesis of boronated nucleic acid and protein components is discussed. Results of biological and clinical studies of some boronated nucleosides, nucleotides, amino acids and peptides are presented. CONCLUSION Boronated nucleosides, amino acids and peptides can be considered as potential targeting agents for BNCT.

Synthesis of novel boron-containing polyamines—Agents for DNA targeting in Neutron Capture Therapy

Abstract A new class of carriers for Neutron Capture Therapy, boronated polyamines, are presented that may possess a high affinity for DNA and rapid/specific uptake in brain tumors by comparison with adjacent normal brain. Two first boron-containing polyamines such as 1,8-diamino-4-(4-o-carboranylbutyl)-4-azaoctane and 1,8-diamino-4-(3-o-carbonylpropyl)-4-azaoctane were synthesized via silylation-alkylation reaction of bis-Boc-protected spermidine with either carboranyl iodides or tosylates.

Synthesis and Evaluation of Carborane-Containing Amino Acids for Boron Neutron Capture Therapy

Malignant melanoma, a neoplasm derived from neuroectodermal cells, is usually cutaneous in origin but can arise in a wide variety of extracutaneous sites including the oral, rectal and vaginal mucosa and the eye. It has a high propensity to metastasize to the brain, is usually multicentric, and for all intents and purposes is totally refractory to any current therapeutic modalities. For this reason it is a possible candidate for Boron Neutron Capture Therapy. Although melanoma cells are variably resistant to photon irradiation, they are highly sensitive to alpha-particles.

New Small Molecular Weight Agents for Boron Neutron Capture Therapy

The development of new BNCT agents requires a priori that the compounds that are synthesized possess the capability of distinguishing between tumor, contiguous normal tissues and other tissues in the path of the neutron beam. This must be achieved not in trace amounts but in levels of the order of 20–50 micrograms of B-10 per gram of tumor or approximately 109 boron atoms per cell1. The question which has plagued the synthetic chemists involved is how can this be accomplished? Information derived from cancer chemotherapy has not been helpful per se since the basis for success or failure of such agents has been strictly a biological and not a concentration endpoint. In the case of radiopharmaceuticals used as cancer diagnostic agents, the chemical amounts are at such trace levels that one cannot extrapolate from this information to estimate what would be the concentration and tissue differentials expected where significant amounts of material are administrated as required for BNCT.

SYNTHESIS OF NEW CARBORANE-CONTAINING KETONES. NOVEL DEHYDROCYANATION REACTION INVOLVING BORON HYDRIDES

A novel dehydrocyanation reaction involving boron hydrides is described. This reaction has been applied to the synthesis of new boronated ketones: di(o-carboran-1-ylmethyl)ketone (8a) and (o-carboran-l-ylmethyl)benzylketone (fib). The stepwise alkylation of commerciallyavailable N-(diphenylmethylene)aminoacetonitrile yielded a,a-disubstituted-[N-(diphenylmethylene)]aminoacetonitriles, 4, which, when reacted with decaborane-acetonitrile complex, undergoes the elimination of hydrogen cyanide. The acid hydrolysis of these dehydrocyanation products, 3. afforded the corresponding ketones, g. Introduction Generally, the better leaving groups in organic structures are those that are the conjugate bases of strong acids. By that criterion alone, the cyano would be considered to be a very poor leaving group (pKa of HCN is 9.22). However, there are examples of dehydrocyanation reactions involving alkylated α-aminonitriles.· Usually, these involve the use of strong bases, elevated temperatures or a combination of both, with the generation of substituted enamines. During the course of synthesizing a series of carborane-containing amino acids, we observed a novel dehydrocyanation reaction that occurred in the preparation of carboranes derived from a,a-disubstituted-[N-(diphenylmethylene)]aminoacetonitriles. In this paper, we have explored the generality of this novel elimination reaction and a possible mechanism by which the cyano function has become activated and thereby has been transformed into a leaving group. Results and Discussion In a previous paper, the synthesis of ocaiboranylalanine is described that involved phase transfer alkylation, boronation and hydrolysis of N-(diphenylmethylene)aminoacetonitrile. The sole product in high yield was the expected amino acid. When the same procedure was applied to the synthesis of a,a-di(ocarboran-1-ylmethyl)glycine, a second product was obtained, in the boronation reaction, which was unexpected. Alkylation of 3-(o-carboranyl-1-yl)-2-[N(diphenylmethylene)]aminopropionitrile, la , with propargyl bromide yielded the desired compound 2a (Scheme 1). Boronation of 2a with bis-acetonitrile-decaborane furnished 4a but in addition a second product 3a. As the reaction progressed the amount of 3a increased at the expense of 4aStructure determination of both products showed 3a to be 1,3-di(o-carboran-1-yl)-2-[N(diphenylmethylene)]amino-prop-1-ene and 4a to be 2-(ocarboran-1-ylmethyl)-3-(ocarboran-1yl)-2-[N-(diphenylmethylene)]aminopropionitrile. Therefore compound 3a was the product of an unusual dehydrocyanation of 4a. The same dehydrocyanation was observed for the boronation of 3-phenyl-2-(prop-1 -ynyl)-2-[N-(diphenylmethylene)}-aminopropionitrile (2b) with decaboraneacetonitrile complex. The formation of two products: 3fe (product of boronation-dehydrocyanation) and 4fe (product of boronation) was detected and their structures were confirmed by HR MS, 1 H and C NMR spectra. It is noteworthy that the extended time of boronation yielded only 3a or 3b. respectively.

Approaches to the Design and Evaluation of Compounds for BNCT

The development of new and more effective agents for neutron capture therapy (NCT) continues to remain an important and ongoing problem as we strive to prepare compounds which possess greater and greater specificity for tumor versus contiguous normal tissues1. The problem that the synthetic chemist encounters in the rational development of such compounds is the paucity of information available as to the biochemical and physiological differences between normal and malignant cells that will allow the selective incorporation of the neutron absorber into tumor cells and their stroma. Cancer chemotherapeutic agents2 which have been used clinically for more than 40 years, have been evaluated for their tumoricidal activity and not on the basis of concentration differentials that may exist between tumor and adjacent normal tissues. On the other hand, concentration differentials have been very important in the development of radiopharmaceuticals, which have been used largely as diagnostic agents for malignancies, but in such instances only trace amounts, from a chemical standpoint, are administered3. Therefore, it is understandable that their clinical pharmacokinetic parameters may be considerably different from those observed, where significant amounts of compound are administered. This is certainly the requirement for NCT. Thus, the key questions for the development of new compounds for NCT are: (1) what is the rational basis for designing specific tumor-targeting agents, and (2) how should such structures be evaluated from an in vitro and in vivo standpoint in order to ascertain their potential utility in NCT?