Cyclohexenylboration of Aldehydes and Ketones with the Borabicyclo[3.3.2]decanes (BBDs).

Asymmetric hydroboration of 1,3-cyclohexadiene with 4R produces the allylborane 5RR as essentially a single diastereomer (i.e., no observable 5RS), and its addition to representative aldehydes provides 9RS (52-75%) with excellent selectivity (94-99% ee). By contrast, a similar sequence with the 10-Ph-BBD reagent, 14R, results in a ca. 45:55 mixture of 15RR and 15RS. However, their addition to methyl ketones provides the corresponding 3°-homoallylic alcohols (18RS) with excellent selectivity (80-99% ee) but in low yields (15-52%) because 15RS is unreactive toward either allylboration or isomerization to 15RR. Thus, with 2 equiv of 15, the yield of 18 (R = Ph) is increased from 52% to 85%. Boranes 5SS and 15SS provide enantiomeric alcohols.

Synthesis of [(18)F]FMISO in a flow-through microfluidic reactor: Development and clinical application.

INTRODUCTION: The PET radiotracer [(18)F]FMISO has been used in the clinic to image hypoxia in tumors. The aim of the present study was to optimize the radiochemical parameters for the preparation of [(18)F]FMISO using a microfluidic reaction system. The main parameters evaluated were (1) precursor concentration, (2) reaction temperature, and (3) flow rate through the microfluidic reactor. Optimized conditions were then applied to the batch production of [(18)F]FMISO for clinical research use. METHODS: For the determination of optimal reaction conditions within a flow-through microreactor synthesizer, 5-400 µL the precursor and dried [(18)F]fluoride solutions in acetonitrile were simultaneously pushed through the temperature-controlled reactor (60-180 °C) with defined flow rates (20-120 µL/min). Radiochemical incorporation yields to form the intermediate species were determined using radio-TLC. Hydrolysis to remove the protecting group was performed following standard vial chemistry to afford [(18)F]FMISO. RESULTS: Optimum reaction parameters for the microfluidic set-up were determined as follows: 4 mg/mL of precursor, 170 °C, and 100 µL/min pump rate per reactant (200 µL/min reaction overall flow rate) to prepare the radiolabeled intermediate. The optimum hydrolysis condition was determined to be 2N HCl for 5 min at 100 °C. Large-scale batch production using the optimized conditions gave the final, ready for human injection [(18)F]FMISO product in 28.4 ± 3.0% radiochemical yield, specific activity of 119 ± 26 GBq/µmol, and >99% radiochemical and chemical purity at the end of synthesis (n = 4). CONCLUSION: By using the NanoTek microfluidic synthesis system, [(18)F]FMISO was successfully prepared with good specific activity and high radiochemical purity for human use. The product generated from large-scale batch production using flow chemistry is currently being used in clinical research.

Synthesis of PEG-supported organotrifluoroborates and their applications in palladium-catalyzed homo-coupling reactions.

A general synthetic route to water-soluble PEG-supported organotrifluoroborates has been developed. In the presence of air and catalytic amounts of Pd(OAc)2, the PEG-supported organotrifluoroborates undergo homo-coupling reactions smoothly at room temperature. No additional oxidizing agent, base, or phosphine ligands are required.

Effects of l-DOPA pre-loading on the uptake of boronophenylalanine using the F98 glioma and B16 melanoma models.

The present study was undertaken to evaluate the effects of l-DOPA pre-loading on the uptake of BPA using the F98 rat glioma and the murine B16 melanoma models. In vitro pretreatments of F98 glioma and B16 melanoma cells with l-DOPA, followed by exposure to BPA increased boron uptake, as determined by inductively coupled plasma-optical emission spectroscopy (ICP-OES). Based on this, in vivo studies were initiated in F98 glioma bearing rats. Initially, the l-DOPA dosing paradigm was evaluated. Maximum tumor boron uptake was observed following i.p. administration of l-DOPA (50mg/kg) followed 24h later by BPA (31.8±8.9 vs. 17.2±6.3µg/g for BPA alone). Next, the effect of l-DOPA pre-loading as a function of the route of administration of BPA was evaluated in F98 glioma bearing rats. The greatest increase in uptake was seen following i.v. administration of BPA, while in contrast no significant increase was seen following intracarotid (i.c.) administration (38.6±12.4 vs. 34.2±10.9). Cellular localization of the F98 glioma, as determined by secondary ion mass spectrometry (SIMS) boron imaging revealed equivalent tumor boron concentrations following l-DOPA pre-loading. In vivo studies in B16 melanoma bearing mice showed equivalent tumor boron values in treated and untreated mice, suggesting that the effects of l-DOPA pre-loading may depend both on the histologic type of tumor and its anatomic site.

Evaluation of unnatural cyclic amino acids as boron delivery agents for treatment of melanomas and gliomas.

Unnatural cyclic amino acids (UNAAs) are a new class of boron delivery agents that are in a pre-clinical stage of evaluation. In the present study, the biodistribution of racemic forms of the cis- and trans-isomers of the boronated UNAA 1-amino-3-boronocyclopentanecarboxylic acid (ABCPC) and 1-amino-3-boronocycloheptanecarboxylic acid (ABCHC) were evaluted in B16 melanoma bearing mice and this was compared to l-p-boronophenylalanine (BPA). Boron concentrations were determined by inductively coupled plasma-optical emission spectroscopy (ICP-OES) at 2.5h following intraperitoneal (i.p.) injection of the test agents at a concentration equivalent to 24mg/B/kg. While all compounds attained comparable tumor boron concentrations, the tumor/blood (T/Bl) boron concentration ratios were far superior for both cis-ABCPC and cis-ABCHC compared to BPA (T/Bl=16.4, and 15.1 vs. 5.4). Secondary ion mass spectrometry (SIMS) imaging revealed that the cis-ABCPC delivered boron to the nuclei, as well as the cytoplasm of B16 cells. Next, a biodistribution study of cis-ABCPC and BPA was carried out in F98 glioma bearing rats following i.p. administration. Both compounds attained comparable tumor boron concentrations but the tumor/brain (T/Br) boron ratio was superior for cis-ABCPC compared to BPA (6 vs. 3.3). Since UNAAs are water soluble and cannot be metabolized by tumor cells, they could be potentially more effective boron delivery agents than BPA. Our data suggest that further studies are warranted to evaluate these compounds prior to the initiation of clinical studies.

Biodistribution and subcellular localization of an unnatural boron-containing amino acid (cis-ABCPC) by imaging secondary ion mass spectrometry for neutron capture therapy of melanomas and gliomas.

The development of new boron-delivery agents is a high priority for improving the effectiveness of boron neutron capture therapy. In the present study, 1-amino-3-borono-cyclopentanecarboxylic acid (cis-ABCPC) as a mixture of its L- and D-enantiomers was evaluated in vivo using the B16 melanoma model for the human tumor and the F98 rat glioma as a model for human gliomas. A secondary ion mass spectrometry (SIMS) based imaging instrument, CAMECA IMS 3F SIMS Ion Microscope, was used for quantitative imaging of boron at 500 nm spatial resolution. Both in vivo and in vitro studies in melanoma models demonstrated that boron was localized in the cytoplasm and nuclei with some cell-to-cell variability. Uptake of cis-ABCPC in B16 cells was time dependent with a 7.5:1 partitioning ratio of boron between cell nuclei and the nutrient medium after 4 hrs. incubation. Furthermore, cis-ABCPC delivered boron to cells in all phases of the cell cycle, including S-phase. In vivo SIMS studies using the F98 rat glioma model revealed an 8:1 boron partitioning ratio between the main tumor mass and normal brain tissue with a 5:1 ratio between infiltrating tumor cells and contiguous normal brain. Since cis-ABCPC is water soluble and can cross the blood-brain-barrier via the L-type amino acid transporters (LAT), it may accumulate preferentially in infiltrating tumor cells in normal brain due to up-regulation of LAT in high grade gliomas. Once trapped inside the tumor cell, cis-ABCPC cannot be metabolized and remains either in a free pool or bound to cell matrix components. The significant improvement in boron uptake by both the main tumor mass and infiltrating tumor cells compared to those reported in animal and clinical studies of p-boronophenylalanine strongly suggest that cis-ABCPC has the potential to become a novel new boron delivery agent for neutron capture therapy of gliomas and melanomas.

Boronated carbohydrate derivatives as potential boron neutron capture therapy reagents.

The treatment of cancer remains one of the most challenging problems for humanity. Boron neutron capture therapy is a binary approach for cancer treatment that is particularly attractive in treating high-grade gliomas and metastatic brain tumors. Among the types of boron-containing molecules used as boron neutron capture therapy agents, boronated carbohydrate derivatives have received significant attention because of their preferential uptake by growing tumor cells. This review provides a summary of the recent developments in the chemistry of carborane-containing carbohydrates.

Microwave-enhanced cross-coupling reactions involving alkynyltrifluoroborates with aryl bromides.

Palladium-catalyzed alkynylation has emerged as one of the most reliable methods for the synthesis of alkynes which are often used in natural product syntheses and material science. An efficient method for coupling alkynyltrifluoroborates with various aryl bromides in the presence of a palladium catalyst has been developed using microwave irradiation. The microwave reactions are rapid and efficient.

A rapid microfluidic synthesis of [18F]fluoroarenes from nitroarenes.

Microfluidic radiofluorodenitrations have been successfully performed using a commercially available microfluidic synthesis system. Reactions of nitroarenes with para-substituted electron withdrawing groups provide incorporation yields ranging from 43 to 97%. Ortho- and meta-substituted nitroarenes provided incorporation yields up to 35%. The reactions were conducted using dry, no-carrier-added [(18)F]-fluoride and K(2)CO(3)/K(222) dissolved in N,N-dimethylformamide or dimethyl sulfoxide with total synthesis times of less than five min. The methodology developed in these studies can be applied to the synthesis of a variety of fluorine-18 labeled radiotracers and radiolabeled prosthetic groups from nitroarene precursors.

Hydrogenolysis-hydrogenation of aryl ethers: selectivity pattern.

The selectivity pattern of nickel-catalyzed hydrogenolysis-hydrogenation of aryl ethers has been studied in the micellar media. The micellar conditions selectively formed arenes and alcohols with enhanced yields.

A novel catalytic process for trifluoromethylation of bromoaromatic compounds.

The palladium-catalyzed trifluoromethylation of aryl bromides has been achieved in micellar media. The micellar conditions result in enhanced yields and are applicable to bromoaromatics with ketone, aldehyde, hydroxyl and amine functionalities.

Boronated unnatural cyclic amino acids as potential delivery agents for neutron capture therapy.

Boron delivery characteristics of cis and trans isomers of a boronated unnatural amino acid, 1-amino-3-boronocyclopentanecarboxylic acid (ABCPC) were tested in the B16 mouse model for human melanoma. Both ABCPC isomers delivered comparable boron to B16 melanoma tumor cells as L-p-boronophenylalanine (BPA). Secondary ion mass spectrometry (SIMS) analysis revealed the presence of boron throughout the tumor from these compounds, and a near homogeneous distribution between the nucleus and cytoplasm of B16 cells grown in vitro. These encouraging observations support further studies of these new boron carriers in BNCT.

Design, synthesis, and biological evaluation of 4-(5-dimethylamino-naphthalene-1-sulfon-amido)-3-(4-iodophenyl)butanoic acid as a novel molecular probe for apoptosis imaging.

Apoptosis (programmed cell death) plays a crucial role in the pathogenesis of many disorders, thus the detection of apoptotic cells can provide the physician with important information to further therapeutic strategies and would substantially advance patient care. A small molecule, 4-(5-dimethylamino-naphthalene-1-sulfonamido)-3-(4-iodo-phenyl)butanoic acid (DNSBA), was designed as a novel probe for imaging apoptosis and synthesized with good yield. The biological characterization demonstrated that DNSBA can be used to specifically and selectively detect apoptotic cancer cells at all stages. DNSBA is also designed as a potential SPECT and PET probe when labeled with radioiodine (I-123, -124, and -131).

Design and synthesis of novel derivatives of all-trans retinoic acid demonstrate the combined importance of acid moiety and conjugated double bonds in its binding to PML-RAR-alpha oncogene in acute promyelocytic leukemia.

The binding of all-trans retinoic acid (ATRA) to retinoid receptor-alpha (RAR-alpha) relieves transcriptional repression induced by the promyelocytic leukemia-retinoic acid receptor (PML-RAR) oncoprotein. The ATRA molecule contains a cyclohexenyl ring, a polyene chain containing conjugated double alkene bonds, and a terminal carboxyl group. To determine the contributions of these structural components of ATRA to its clinical efficacy, we synthesized three novel retinoids. These consisted of either a modified conjugated alkene backbone with an intact acid moiety (13a) or a modified conjugated alkene backbone and conversion of the acid group to either an ester (13b) or an aromatic amide (13c). Reporter assays demonstrated that compound 13a successfully relieved transcriptional repression by RAR-alpha, while 13b and 13c could not, demonstrating the critical role of the acid moiety in this binding. However, only ATRA was able to significantly inhibit the proliferation of APL cells while 13a, 13b, or 13c was not. Furthermore, only 13a led to partial non-significant differentiation of NB4 cells, demonstrating the importance of C9-C10 double bonds in differentiation induced CD11 expression. Our results demonstrate that both the acid moiety and conjugated double bonds present in the ATRA molecule are important for its biological activity in APL and have important implications for the design of future novel retinoids.

Syntheses and characterization of polymer-supported organotrifluoroborates: applications in radioiodination reactions.

A novel strategy combining the advantages of polymer-supports and organotrifluoroborate chemistry for radiotracer preparation is reported.

Chemoselective bromodeboronation of organotrifluoroborates using tetrabutylammonium tribromide: application in (Z)-dibromoalkene syntheses.

Tetrabutylammonium tribromide (TBATB) has been found to be a unique bromodeboronation reagent for organotrifluoroborates. When compared to previously reported bromodeboronation methods, the mild and metal-free reaction conditions tolerate a wider range of functional groups. High regio- and chemoselectivity are observed in the presence of both unsaturated carbon-carbon bonds and aldehyde functional groups. An efficient synthetic route to (Z)-dibromoalkenes from terminal alkynes has been developed using the TBATB-mediated bromodeboronation as a key step.

Titanium(IV) halide mediated coupling of alkoxides and alkynes: an efficient and stereoselective route to trisubstituted (E)-alkenyl halides.

Alkoxide C-O bond cleavage occurs readily at room temperature in the presence of titanium(IV) halide. Capture of the resultant carbocation by alkynes provides an efficient route to trisubstituted (E)-alkenyl halides with high stereoselectivity.

Design and synthesis of (E)-1-((3-ethyl-2,4,4-trimethylcyclohex-2-enylidene)methyl-4-substituted benzenes from 1-(2,6,6-trimethylcyclohex-1-enyl)ethanol.

A novel strategy for synthesizing (E)-1-((3-ethyl-2,4,4-trimethylcyclohex-2-enylidene)methyl-4-substituted benzenes from 1-(2,6,6-trimethylcyclohex-1-enyl)ethanol has been developed; the allylic alcohol was treated with PPh(3).HBr in methanol followed by aldehydes in the presence of a base and furnished the 1,3-dienes in moderate to good yields (79-86%).

Implications for clinical treatment from the micrometer site dosimetric calculations in boron neutron capture therapy.

Boron neutron capture therapy has now been used for several malignancies. Most clinical trials have addressed its use for the treatment of glioblastoma multiforme. A few trials have focused on the treatment of malignant melanoma with brain metastases. Trial results for the treatment of glioblastoma multiforme have been encouraging, but have not achieved the success anticipated. Results of trials for the treatment of malignant melanoma have been very promising, though with too few patients for conclusions to be drawn. Subsequent to these trials, regimens for undifferentiated thyroid carcinoma, hepatic metastases from adenocarcinoma of the colon, and head and neck malignancies have been developed. These tumors have also responded well to boron neutron capture therapy. Glioblastoma is an infiltrative tumor with distant individual tumor cells that might create a mechanism for therapeutic failure though recurrences are often local. The microdosimetry of boron neutron capture therapy can provide an explanation for this observation. Codes written to examine the micrometer scale energy deposition in boron neutron capture therapy have been used to explore the effects of near neighbor cells. Near neighbor cells can contribute a significantly increased dose depending on the geometric relationships. Different geometries demonstrate that tumors which grow by direct extension have a greater near neighbor effect, whereas infiltrative tumors lose this near neighbor dose which can be a significant decrease in dose to the cells that do not achieve optimal boron loading. This understanding helps to explain prior trial results and implies that tumors with small, closely packed cells that grow by direct extension will be the most amenable to boron neutron capture therapy.

Identification of a boron-containing intermediate in the boron tribromide mediated aryl propargyl ether cleavage reaction.

An alternate reaction mechanism for the boron tribromide mediated deprotection of aryl propargyl ethers based on the isolation of a key boron-containing byproduct is proposed. On the basis of the new mechanistic insight, we discovered that HBBr(2) x SMe(2) can also be used for cleaving aryl propargyl ethers.