Synthesis and Anticancer Activities of Novel Guanylhydrazone and Aminoguanidine Tetrahydropyran Derivatives.

In this paper we present the convenient syntheses of six new guanylhydrazone and aminoguanidine tetrahydropyran derivatives 2-7. The guanylhydrazone 2, 3 and 4 were prepared in 100% yield, starting from corresponding aromatic ketones 8a-c and aminoguanidine hydrochloride accessed by microwave irradiation. The aminoguanidine 5, 6 and 7 were prepared by reduction of guanylhydrazone 2-4 with sodium cyanoborohydride (94% yield of 5, and 100% yield of 6 and 7). The aromatic ketones 8a-c were prepared from the Barbier reaction followed by the Prins cyclization reaction (two steps, 63%-65% and 95%-98%). Cytotoxicity studies have demonstrated the effects of compounds 2-7 in various cancer and normal cell lines. That way, we showed that these compounds decreased cell viabilities in a micromolar range, and from all the compounds tested we can state that, at least, compound 3 can be considered a promising molecule for target-directed drug design.

Ammine Calcium and Strontium Borohydrides: Syntheses, Structures, and Properties.

A new series of solvent- and halide-free ammine strontium metal borohydrides Sr(NH3 )n (BH4 )2 (n=1, 2, and 4) and further investigations of Ca(NH3 )n (BH4 )2 (n=1, 2, 4, and 6) are presented. Crystal structures have been determined by powder XRD and optimized by DFT calculations to evaluate the strength of the dihydrogen bonds. Sr(NH3 )(BH4 )2 (Pbcn) and Sr(NH3 )2 (BH4 )2 (Pnc2) are layered structures, whereas M(NH3 )4 (BH4 )2 (M=Ca and Sr; P21 /c) are molecular structures connected by dihydrogen bonds. Both series of compounds release NH3 gas upon thermal treatment if the partial pressure of ammonia is low. Therefore, the strength of the dihydrogen bonds, the structure of the compounds, and the NH3 /BH4 (-) ratio for M(NH3 )n (BH4 )m have little influence on the composition of the released gasses. The composition of the released gas depends mainly on the thermal stability of the ammine metal borohydride and the corresponding metal borohydride.

New functionalized mercaptoundecahydrododecaborate derivatives for potential application in boron neutron capture therapy: synthesis, characterization and dynamic visualization in cells.

A series of mercaptoundecahydrododecaborate (B12H11SH(2-), BSH) bearing mono- and dicarboxyalkyl derivatives was prepared, characterized, and their reactivity towards amidation and esterification in DMF was evaluated. Symmetrical alkylation of BSH was achieved by treatment with primary haloalkyl carboxylic acids in aqueous acetonitrile to produce S,S-bis(carboxyalkyl)sulfonium-undecahydro-closo-dodecaborate tetramethylammonium salts. Unsymmetrically substituted sulfonium salts were obtained through a similar treatment of cyanoethylthioether-undecahydro-closo-dodecaborate tetramethylammonium salt with haloalkyl carboxylic acid. Selective removal of the remaining cyanoethyl group upon treatment with tetramethylammonium hydroxide yielded S-carboxyalkyl-thioether-undecahydro-closo-dodecaborate ditetramethylammonium salts. N,N'-dicyclohexylcarbodiimide (DCC) activated amidation of S,S-bis(carboxyalkyl)sulfonium-undecahydro-closo-dodecaborate or S-carboxyalkyl-thioether-undecahydro-closo-dodecaborate tetramethylammonium salts with propargylamine provided the opportunity to install terminal acetylene groups for further conjugation. These compounds acted as powerful building blocks for the synthesis of a broad range of 1,4-disubstituted 1,2,3-triazole products in high yields, utilizing the Cu(I)-mediated click cycloaddition reaction. The synthesis of BSH-lipid with a two-tailed moiety was also achieved, by esterification of S,S-bis(carboxyethyl)sulfoniumundecahydro-closo-dodecaborate(1-) tetramethylammonium salt with 1,2-O-distearoyl-sn-3-glycerol, which may prove useful in the liposomal boron delivery system. The bio-compatibility of the azide-alkyne click reaction was then utilized by performing this reaction in cell culture. The distribution of BSH in HeLa cells could be visualized by treating the cells first with a BSH-alkyne compound and then with Alexa Fluor 488(®) azide dye. The BSH-dye conjugate, which did not wash out, revealed the distribution of boron in the HeLa cells. Cytotoxicity assays of these BSH derivatives revealed that the synthesized BSH-conjugated triazoles possessed low cytotoxicity in HeLa cancer cells. Of these compounds, BSH conjugated triazole 15 induced a significant increase in the level of boron accumulation in HeLa cells.

Deprotonation of a borohydride: synthesis of a carbene-stabilized boryl anion.

An acidic hydride! Thanks to the presence of a π-acceptor cyclic alkyl amino carbene and of two electron-withdrawing nitrile groups, a borohydride reacts with a base to give a carbene-stabilized boryl anion, which reacts with carbon and metal electrophiles at the boron center. Dipp = 2,6-diisopropylphenyl, KHMDS = potassium bis(trimethylsilyl)amide.

Syntheses and structures of lanthanide borohydrides supported by a bridged bis(amidinate) ligand and their high activity for controlled polymerization of ε-caprolactone, L-lactide and rac-lactide.

Metathesis reaction of LLnCl(THF)(2) [L = (Me(3)SiNC(C(6)H(5))N)(2)(CH(2))(3)] with NaBH(4) in a 1 : 1.5 molar ratio in THF (THF = tetrahydrofuran) at 60 °C afforded the monoborohydride LLn(BH(4))(DME) [Ln = Y (1), Nd (2), Sm(3) and Yb(4)] crystallized from DME solution (DME = dimethoxyethane). Crystal structure analyses revealed 1-4 are monomers, in which each metal is ligated by one L ligand, one η(3)-BH(4) group and one DME molecule in a trigonal bipyramid geometry. Complexes 1-4 were found to be very active single-site initiators for the controlled ring opening polymerization of ε-caprolactone (ε-CL) and L-lactide (L-LA) as judged by relatively narrow molecular weight distributions (M(w)/M(n): 1.34-1.50) and experimental values M(n)(exp) were in good agreement with theoretic values M(n)(theo). The highest activity and the best control over the molecular weight for both monomers were found for the system with 2. These monoborohydride complexes can also initiate the ring opening polymerization of rac-LA to gave heterotactically enriched polyLA with Pr (heterotactic enrichment) values in a range of 0.69-0.85 depending on the lanthanide metals and the most effective heterotactic enrichment (Pr) was found for 1 (Pr = 0.85). Moreover, complex 1 initiated the polymerization of rac-LA in a living fashion.

Transition-metal-catalyzed synthesis of diboranes(4).

The diboranes(4) bis(catecholato)diborane (B(2)Cat(2)) and bis(pinacolato)diborane (B(2)Pin(2)) are important precursors for organoboronic esters, which are versatile reagents for the formation of carbon-carbon bonds. A new catalytic synthesis for these compounds starts from catecholborane or pinacolborane and gives the dehydrocoupling products B(2)Cat(2) and B(2)Pin(2) with turnover numbers of up to 11,600 (see scheme).

Highly volatile magnesium complexes with the aminodiboranate anion, a new chelating borohydride. Synthesis and characterization of Mg(H(3)BNMe(2)BH(3))(2) and related compounds.

Remarkably volatile magnesium complexes have been prepared with the modified borohydride ligand N,N-dimethylaminodiboranate, H(3)BNMe(2)BH(3)(-). The homoleptic complex Mg(H(3)BNMe(2)BH(3))(2), its monoadducts with tetrahydrofuran and 1,2-dimethoxyethane, and the mixed ligand complex (C(5)Me(5))Mg(H(3)BNMe(2)BH(3))(thf) have been prepared. The homoleptic complex Mg(H(3)BNMe(2)BH(3))(2) has a vapor pressure of 800 mTorr at 25 degrees C, which makes it the most volatile magnesium complex known. Crystal structures and NMR data are reported for all complexes. The compounds are potentially useful as chemical vapor deposition precursors to MgB(2) and MgO, and as hydrogen storage materials.

New strategy for synthesis of mercaptoundecahydrododecaborate derivatives via click chemistry: possible boron carriers and visualization in cells for neutron capture therapy.

A new method that utilizes the click cycloaddition reaction to functionalize B(12)H(11)SH(2-) (BSH) with organic molecules was investigated. S,S-Dipropargyl-SB(12)H(11)(-) (1) and S-propargyl-SB(12)H(11)(2-) (4) were prepared from [(CH(3))(4)N](2)B(12)H(11)SH and [(CH(3))(4)N](2)B(12)H(11)S(CH(2))(2)CN (2) with propargyl bromide, respectively. Compound 1 or 4 reacted with various azides with mediation by Cu(II) ascorbate to give the corresponding bis-triazolo BSH derivatives (1-) or monotriazole BSH derivatives (2-), respectively, in excellent yields. The click cycloaddition reaction is very useful not only for the synthesis of various BSH-containing organic compounds for boron neutron capture therapy (BNCT) but also for the visualization of boron clusters in cells. We succeeded in the click cycloaddition reaction of compound 1 with Alexa Fluor 488 azide dye and found that 1 accumulated not in the cytoplasm but in the nuclei of HeLa cells.

Controlled in-situ synthesis of silver nanoparticles in natural cellulose fibers toward highly efficient antimicrobial materials.

In this report, we presented in-situ synthesis of silver nanoparticles in natural cellulose fibers which embody high oxygen (ether and hydroxyl) density and could be considered as aggregated nanoreactors and stabilizers for the nucleation and growth of silver nanoparticles. The morphologies of natural cellulose fibers and silver nanoparticles were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), and UV-visible spectroscopy. The content of silver nanoparticles in cellulose fibers was measured by inductive coupled plasma-mass spectrometry (ICP-ms). Experimental results revealed that sodium borohydride (NaBH4) played dual effects in the formation of silver nanoparticles. The mean size (d) and size distribution (sigma) of silver nanoparticles could be adjusted by changing the concentration of NaBH4. Monodisperse silver nanoparticles (d = 2.7 nm, sigma = 0.6 nm) in cellulose fibers were successfully prepared under optimized conditions. When the NaBH4 concentration was very low (0.1 mM), a stable colloidal solution (storage stability > 1 month) of silver nanoparticles was produced, which provides a novel, mild approach to the preparation of stable colloidal solutions of metal nanoparticles. The ability of silver nanoparticle-loaded cellulose fibers to prohibit the propagation of Escherichia coli was estimated by the Minimum Inhibitory Concentration (MIC). Based on the experimental observations, the antibacterial mode of silver nanoparticle-loaded cellulose fibers was discussed in details.

Speciation of butyltin compounds in environmental and biological samples using headspace single drop microextraction coupled with gas chromatography-inductively coupled plasma mass spectrometry.

A method based on headspace single drop microextraction (HS-SDME) in combination with gas chromatography-inductively coupled plasma mass spectrometry (GC-ICP-MS) was proposed for the speciation analysis of butyltin compounds in environmental and biological samples. The sodium tetraethylborate (NaBEt4) and sodium tetrahydroborate (NaBH4) were used as the derivatizing reagent for in situ derivatization of the butyltins. For the two derivatizations, the HS-SDME parameters such as organic solvent, drop volume, sample pH, stirring rate, temperature, extraction time and the ionic strength were examined systematically. The analytical performance including the linearity ranges, limits of detection (LODs) and reproducibilities of the two derivatizations were compared under the respective optimized conditions. Derivatization with NaBEt(4) proved to be more sensitive and robust than that with NaBH4, leading to the LODs of 1.4 ng/L for MBT, 1.8 ng/L for DBT and 0.8 ng/L for TBT. The reproducibilities, expressed as relative standard deviations (RSDs), were in the range of 1.1-5.3% (c=1 microg/L, n=3). With tripropyltin (TPrT) as internal standard, HS-SDME-GC-ICP-MS with NaBEt(4) derivatization was applied for the speciation analysis of butyltins in real seawater and shellfish samples. The butyltins found in the real-world samples are 31ng/L MBT, 79 ng/L DBT and 32 ng/L TBT for seawater, and 11.6-30.4 ng/g MBT, 11.8-8.9 ng/g DBT and 12.8-52.6 ng/g TBT for different shellfish samples. For validation, the developed method was also employed for the speciation analysis of butyltins in certified reference material (CRM) of PACS-2 sediment, and the determined values are in a good agreement with the certified values. The developed method is simple, rapid, sensitive, and cost-effective and provides an attractive alternative for butyltins speciation in biological and environmental samples with complex matrix.

Evaluation of hypoxia-specific cytotoxic bioreductive agent-sodium borocaptate-10B conjugates as 10B-carriers in boron neutron capture therapy.

PURPOSE: To evaluate the usefulness of 5 new 10B-compounds (TX-2091, TX-2095, TX-2097, TX-2100, and TX-2110) as 10B-carriers in boron neutron capture therpy (BNCT). They were conjugates that had been synthesized from a hypoxia-specific cytotoxic bioreductive agent, quinoxaline oxide TX-402, and a clinically used 10B-carrier, sodium borocaptate-10B (BSH). MATERIALS AND METHODS: The 5 new compounds were hybrid compounds that have both a hypoxic cytotoxin unit and a thermal neutron-sensitizing unit, BSH. These new compounds and BSH were administered intraperitoneally to SCC VII tumor-bearing mice. Then, the 10B concentrations in the tumors and normal tissues were measured by gamma-ray spectrometry. Subsequently, SCC VII tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells in the tumors, then treated with TX-2100, which was chosen based on the results of the above-mentioned biodistribution analyses, or BSH in the same manner as in the biodistribution studies. Right after irradiation, during which intratumor 10B concentrations were kept at levels similar to each other, the tumors were excised, minced, and trypsinized. The tumor cell suspensions thus obtained were incubated with cytochalasin-B (a cytokinesis blocker), and the micronucleus (MN) frequency in cells without BrdU labeling [= quiescent (Q) cells] was determined using immunofluorescence staining for BrdU. Meanwhile, the MN frequency in the total (P+Q) tumor cell population was determined from the tumors that were not pretreated with BrdU. Clonogenic cell survival was also determined in mice given no BrdU. RESULTS: 10B biodistribution analyses in tumors, brain, skin, muscles, blood, and liver indicated that TX-2100 has the most favorable characteristics for concentrating a sufficient amount of 10B in tumors and maintaining a high enough 10B concentration during irradiation. In addition, TX-2100 had a significantly stronger radio-sensitizing effect with reactor thermal neutron beams than BSH on both total and Q cells in solid tumors. Further, TX-2100 clearly exhibited a radio-sensitizing effect with gamma-rays not only on total cells but also on Q and hypoxic tumor cells, which was not achieved by BSH. CONCLUSION: A 10B-carrier that acts as a hypoxic cytotoxin on tumor cells as well as having the potential to keep 10B in tumors and sensitize tumor cells more markedly than conventional 10B-carriers, such as TX-2100, is a promising candidate for use in BNCT.

[(Triphos)Ni(eta2-BH4)]: an unusual nickel(I) borohydride complex.

Reduction of [(triphos)NiCl2] (1) with an excess of NaBH4 in THF produces the paramagnetic Ni(I) complex [(triphos)Ni(eta2-BH4)] (2). X-ray crystallography shows 1 to be a square-planar Ni(II) species in which the phosphine ligand is bidentate, whereas 2 has pseudotetrahedral geometry at the Ni(I) center, with a tridentate phosphine and the borohydride ligand occupying a single coordination site. Density functional theory calculations show the unpaired electron in 2 to reside in an orbital located mainly on the Ni atom.

Lanthanide borohydride complexes supported by diaminobis(phenoxide) ligands for the polymerization of epsilon-caprolactone and L- and rac-lactide.

Reaction of Na2O2NN' [H2O2NN' = (2-C5H4N)CH2N[2-HO-3,5-C6H2(t)Bu2]2] with M(BH4)3(THF)3 afforded the dimeric, rare-earth borohydride compounds [M(O2NN')(mu-BH4)(THF)n]2 [M = Y(III), n = 0.5 (1-Y); M = NdIII, n = 1 (1-Nd); M = SmIII, n = 0 (1-Sm)]. For comparison the chloride analogues [M(O2NN')(mu-Cl)(THF)n]2 (2-M; M = La(III) or Sm(III), n = 0; M = Nd(III), n = 1) and the corresponding pyridine adducts [M(O2NN')(mu-X)(py)]2 [X = BH4 (3-M) or Cl (4-M); M = La(III), Nd(III), or Sm(III)] were prepared and structurally characterized for 4-La. Compounds 1-M initiated the ring-opening polymerization of epsilon-caprolactone. The best molecular weight control (suppression of chain transfer) for all three monomers was found for the samarium system 1-Sm. The most effective heterotactic enrichment (Pr) in the polymerization of rac-lactide was found for 1-Y (P(r) = 87%). Compound 1-Nd catalyzed the block copolymerization of epsilon-caprolactone and L- and rac-lactide provided that epsilon-caprolactone was added first. Attempted block polymerization by the addition of L-lactide first, or random copolymerization of a ca. 1:1 mixture of epsilon-caprolactone and L-lactide, gave only a poly(L-lactide) homopolymer.

Addition reactions at the 16(17) double bond of 3-methoxy-13alpha-estra-1,3,5(10),16-tetraene.

The epoxidation, the addition of hypobromous acid, and the hydroboration of 3-methoxy-13alpha-estra-1,3,5(10),16-tetraene 1 with diborane, catecholborane, and 9-BBN were investigated in order to determine the stereochemical outcome and to synthesize new 13alpha-estra-1,3,5(10)-trienes for biological and conformational investigations. It was shown that the sterically demanding reagent 9-BBN participated in a preferred beta attack (53% 16betaOH 10, 34% 17betaOH 8, 13% 16alphaOH 11). This stereochemical result is in agreement with that from another cis addition reaction, the recently described OsO4 dihydroxylation of 1 [Steroids 68 (2003) 113]. With smaller reagents such as B2H6, catecholborane, or magnesium monoperoxyphthalate, a diminished stereoselectivity was observed with only a slight excess of beta attack. The ionic trans addition of hypobromous acid gave two 17-bromo-16-alcohols with 16beta,17alpha (4, 76%) and 16alpha,17beta configuration (5, 24%) formed by trans cleavage of the 16,17alpha- and beta-bromonium ion at position 16. The same regioselective and stereoselective course was found for the cleavage of the 16alpha,17alpha- and 16beta,17beta-epoxides (3 and 2) with hydrazoic acid (3-->16betaN3,17alphaOH 7, 2-->16alphaN3,17betaOH 6). The stereochemistry of the addition reactions to 1 can be explained in terms of a twist-boat conformation involving the C ring of compound 1. From a synthetic viewpoint the synthesis of the beta-epoxide 2 from the bromohydrin 4, the cleavage of this epoxide to 16alpha-substituted-17beta-hydroxy compounds, such as 6, and hydroboration/oxidation with 9-BBN to the hitherto unknown 16beta-hydroxy compound 10 are useful procedures. The bromohydrin 5 is the first 13alpha-steroid with a 17beta-bromo substituent. X-ray analysis revealed twist-boat and 16beta-envelope conformations for rings C and D, respectively.

Preparation of sulfhydrylborane-dextran conjugates for boron neutron capture therapy.

This study presents a carrier system for boron, potentially useful in boron neutron capture therapy (BNCT). Na2B12H11SH (BSH) was covalently coupled to dextran derivatives. This was accomplished in two ways. The first method comprises activation of dextran with 1-cyano-4-(dimethylamino)pyridine (CDAP) with subsequent coupling of 2-aminoethyl pyridyl disulfide (method A). The thiolated dextran could then couple BSH in a disulfide exchange reaction. In the second procedure, dextran was derivatized to a multially derivative (method B) which reacted with BSH in a free-radical-initiated addition reaction. The assessment of boron content of the conjugates was done by elemental analysis of sulfur and atomic spectroscopy of boron (ICP-AES). With method A, only limited numbers of boron cages could be coupled (10-20 cages per dextran chain). With method B, 100-125 boron cages per dextran chain was obtained, corresponding to 1200-1500 boron atoms per dextran chain. This result makes this derivative a promising template for use in the development of BNCT agents.

Technetium-99m complexes of dimethylaminomethylene diphosphonate (DMAD)--I. Anion exchange HPLC characterization of 99mTc(NaBH4)-DMAD mixtures.

Radiopharmaceutical analogs prepared by sodium borohydride reduction of 99mTcO4- in the presence of DMAD have been characterized by anion exchange HPLC (high performance liquid chromatography) separation of the resulting mixture into component 99mTc-DMAD complexes. The distribution of complexes within a radiopharmaceutical formulation can be manipulated by controlling technetium concentration, pH, presence or absence of air, and time post reaction.