Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 6, Issue 2, 2006

Boron is a unique non-metallic element with the ability to combine with itself and many other elements to form compounds of extreme structural diversity and unusual properties. Boron exists in nature as a mixture of two stable isotopes, 10B (19.8%) and 11B (80.2%); the former possesses an extremely high cross-section for neutron capture (3,840 barns), producing high-energy alpha particles and recoiling lithium nuclei, according to the 10B(n,α)7Li nuclear reaction. The discovery of boron clusters of remarkably high boron content in the 1950s and 1960s has widened their application in various fields, mainly in medicinal chemistry as radiolabeling and tumor treatment agents. The exceptional stabilities of boron clusters, their unique hydrophobic and potential amphiphilic properties, and the ability of the opencage clusters to form sandwich complexes with a variety of metals, have led to the development of many interesting molecules for application in tumor imaging and treatment using boron neutron capture therapy (BNCT). Despite extraordinary advances in the last decades on the synthesis and chemistry of boron compounds and their enrichment in the 10B isotope at ∼95% levels, BNCT is still in the early stages of its practical development. One of the main challenges to the BNCT modality continues to be the discovery of uniquely tumor-selective agents, capable of delivering therapeutic concentrations of 10B to target tumors, with low toxicity and high specificity. In this Special Issue of Current Medicinal Chemistry - Anti Cancer Agents, the main classes of boron-containing molecules and the current state-of-the-art in compound design and characterization are reviewed. The scourge of cancer is still with us, but never before has there been such an exciting time in the development of multi-faceted boron molecules for application in medicinal chemistry, and particularly for the treatment of cancer.

The use of polyhedral boron hydrides for cancer treatment is traditionally connected with boron neutron capture therapy. More recently, polyhedral borate anions were proposed as carriers of radionuclide label for targeted radionuclide therapy and diagnostics of cancer. Some metal derivatives of carboranes were found to demonstrate significant antitumor activity themselves. This review is designed to highlight the recent work concerning various fields of potential application of polyhedral boron compounds in anticancer diagnostics and therapy.

The treatment of cancer remains one of the most challenging problems for humanity. Boron neutron capture therapy (BNCT) is a binary approach for cancer treatment that is particularly attractive in treating high-grade gliomas and metastatic brain tumors. Among types of boron-containing molecules used as BNCT agents, boronated amino acids have received significant attention for their preferentially uptake by growing tumor cells. This review emphasizes the synthesis of boronated amino acids.

One category of boron neutron capture therapy (BNCT) agents that has received extensive attention during recent years is 3-carboranyl thymidine analogues (3CTAs). These molecules are phosphorylated to the corresponding 5´- monophosphates by human thymidine kinase 1 (TK1), an enzyme that is up-regulated in dividing malignant cells. Thus, these phosphorylated molecules are selectively entrapped in tumor cells due to the acquired negative charge. This review will analyze design strategies applied for the synthesis of boron-containing nucleosides in general and in particular reference to 3CTAs. Results of biological studies with these molecules will be discussed.

Boronated porphyrins are an important class of tumor-localizing agents in two bimodal therapies for cancer currently under study experimentally and clinically; boron neutron-capture therapy (BNCT) and photodynamic therapy (PDT). The desirable properties for the boronated porphyrins are that they are easily synthesized, pure and wellcharacterized drugs, and that in vivo, they are stable, tumor-specific, with high tumor:blood and tumor:normal tissue boron concentration ratios, and cause minimal toxicity. A large number of new porphyrins and their syntheses are presented herein. The focus is primarily on porphyrins published within the past 5 years, but the implications and trends from porphyrins studied in vivo over the past 15 years are also reviewed. Many possess quite unusual, novel structures and others have appended cell-targeting moieties for greater tumor specificity. Besides the commonly used closo- and nido-ocarboranes other boron cages and modes of attachment are presented. These boron cages can selectively alter the lipophilic, hydrophilic and amphiphilic properties of the porphyrins as well as their boron content. New delivery modalities have also greatly improved the targeting potential of compounds previously deemed unsuitable for applications in BNCT.

The literature on the synthesis and the biological properties of boron-containing chlorins and phthalocyanines is reviewed. A series of homologous derivatives of pyropheophorbide A is described. The compounds contain the B12H11SH2- cluster attached to the single carboxyl group and vary in the length of the alkyl chain (methyl, propyl, pentyl, heptyl and nonyl) attached via an ether linkage to the former vinyl group. Cellular uptake was found for all derivatives except the nonyl sidechain. The compounds were moderately cell-toxic. Localization in lysosomes could be excluded; the compounds localized probably in the mitochondria.

Boron neutron capture therapy (BNCT) is based on the nuclear capture and fission reactions that occur when non-radioactive boron-10 is irradiated with low energy thermal neutrons to yield high linear energy transfer (LET) alpha particles (4He) and recoiling lithium -7(7Li) nuclei. For BNCT to be successful, a sufficient number of 10B atoms (∼ 109 atoms/cell) must be selectively delivered to the tumor and enough thermal neutrons must be absorbed by them to sustain a lethal 10B(n, α) 7Li capture reaction. BNCT primarily has been used to treat patients with brain tumors, and more recently those with head and neck cancer. Two low molecular weight (LMW) boron delivery agents currently are being used clinically, sodium borocaptate and boronophenylalanine. However, a variety of high molecular weight (HMW) agents consisting of macromolecules and nanovehicles have been developed. This review will focus on the latter which include: monoclonal antibodies, dendrimers, liposomes, dextrans, polylysine, avidin, folic acid, and epidermal and vascular endothelial growth factors (EGF and VEGF). Procedures for introducing boron atoms into these HMW agents and their chemical properties will be discussed. In vivo studies on their biodistribution will be described, and the efficacy of a subset of them, which have been used for BNCT of tumors in experimental animals, will be discussed. Since brain tumors currently are the primary candidates for treatment by BNCT, delivery of these HMW agents across the blood-brain barrier presents a special challenge. Various routes of administration will be discussed including receptor-facilitated transcytosis following intravenous administration, direct intratumoral injection and convection enhanced delivery by which a pump is used to apply a pressure gradient to establish bulk flow of the HMW agent during interstitial infusion. Finally, we will conclude with a discussion relating to issues that must be addressed if these HMW agents are to be used clinically.