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PubMed1996

Total Synthesis of (-)-Maytansinol.

A total synthesis of maytansinol (1) was achieved, in a convergent way, using (3S,6S,7S)-aldehyde 4 and (S)-p-tolyl sulfoxide 3 as fragments. When the anion of 3 was condensed with aldehyde 4, some induction at C(10) was observed (60% de), giving the C(1)-N(19)-open-chain compound 7, after thermal elimination of sulfinate. Pure E/E stereochemistry of the 11,13-diene was obtained. Selective modifications of the functionalities permitted macrocyclization and further elaboration to maytansinol.

Journal Article↗
PubMed2006

Boronated protohaemins: synthesis and in vivo antitumour efficacy.

The conjugates of porphyrin macrocycles with boron-containing polyhedra are under investigation as agents for binary treatment strategies of cancer. Aiming at the design of photoactive compounds with low-to-zero dark toxicity, we synthesized a series of carboranyl and monocarbon-carboranyl derivatives of protohaemin IX using the activation of porphyrin carboxylic groups with di-tert-butyl pyrocarbonate or pivaloyl chloride. The water-soluble 1,3,5,8-tetramethyl-2,4-divinyl-6(7)-[2'-(closo-monocarbon-carborane-1''-yl)methoxycarbonylethyl]-7(6)-(2'-carboxyethyl)porphyrin Fe(III) (compound 9) exerted no discernible cytotoxicity for cultured mammalian cells, nor did it cause general toxicity in rats. Importantly, 9 demonstrated dose-dependent activity as a phototoxin in photodynamic therapy of M-1 sarcoma-bearing rats. In animals injected with 20 mg kg(-1) of 9, the tumours shrank by day 3 after one single irradiation of the tumour with red laser light. Between 7 and 14 days post-irradiation, 88.9% of rats were tumour-free; no recurrence of the disease was detectable within at least 90 days. Protohaemin IX alone was without effect, indicating that boronation is important for the phototoxic activity of 9. This is the first study that presents the synthesis and preclinical in vivo efficacy of boronated derivatives of protohaemin as phototoxins. The applicability in photodynamic treatment broadens the therapeutic potential of boronated porphyrins beyond their conventional role as radiosensitizers in boron neutron capture therapy.

Animals↗
PubMed2006

Mixed substituted porphyrins: structural and electrochemical redox properties.

To examine the influence of mixed substituents on the structural, electrochemical redox behavior of porphyrins, two new classes of beta-pyrrole mixed substituted free-base tetraphenylporphyrins H2(TPP(Ph)4X4) (X = CH3, H, Br, Cl, CN) and H2(TPP(CH3)4X4) (X = H, Ph, Br, CN) and their metal (M = Ni(II), Cu(II), and Zn(II)) complexes have been synthesized effectively using the modified Suzuki cross-coupling reactions. Optical absorption spectra of these porphyrins showed significant red-shift with the variation of X in H2(TPPR4X4), and they induce a 20-30 nm shift in the B band and a 25-100 nm shift in the longest wavelength band [Q(x)(0,0)] relative to the corresponding H2TPPR4 (R = CH3, Ph) derivatives. Crystal structure of a highly sterically crowded Cu(TPP(Ph)4(CH3)4).2CHCl3 complex shows a combination of ruffling and saddling of the porphyrin core while the Zn(TPP(Ph)4Br4(CH3OH)).CH3OH structure exhibits predominantly saddling of the macrocycle. Further, the six-coordinated Ni(TPP(Ph)4(CN)4(Py)2).2(Py) structure shows nearly planar geometry of the porphyrin ring with the expansion of the core. Electrochemical redox behavior of the MTPPR4X4 compounds exhibit dramatic cathodic shift in first ring oxidation potentials (300-500 mV) while the reduction potentials are marginally cathodic in contrast to their corresponding MTPPX4 (X = Br, CN) derivatives. The redox potentials were analyzed using Hammett plots, and the highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) gap decreases with an increase in the Hammett parameter of the substituents. Electronic absorption spectral bands of H2TPPR4X4 are unique that their energy lies intermediate to their corresponding data for the H2(TPPX8) (X = CH3, Ph, Br, Cl) derivatives. The dramatic variation in redox potentials and large red-shift in the absorption bands in mixed substituted porphyrins have been explained on the basis of the nonplanarity of the macrocycle and substituent effects.

Crystallography, X-Ray↗
PubMed2006

Electron transfer vs coordination chemistry: isomer-specific binding of HgII by an ortho-Wurster's thiacrown ether.

Isomeric p- and o-phenylenediamine-containing macrocyclic hosts (Wurster's thiacrown ethers L1 and L2, respectively) were prepared and studied as Hg(II) ionophores. The distinct electrochemical properties of the two hosts allowed for the formation of a coordination compound with the ortho-Wurster's thiacrown ether but not the para isomer. In the latter case, the Hg(II) ion served as an oxidant in an electron-transfer reaction with the host. Solutions of the Hg(II) complex of L2 were studied by 13C NMR spectroscopy and cyclic voltammetry and revealed a strong interaction between the redox-active phenylenediamine subunit and the bound metal cation. An X-ray analysis confirmed the participation of the three macrocyclic S atoms and both phenylenediamine N atoms in the stabilization of the complex.

Journal Article↗
PubMed1996

Investigation of enantioselective separation of quinolonecarboxylic acids by capillary zone electrophoresis using vancomycin as a chiral selector.

When a chiral selector that is a pharmaceutical compound is added to the separation buffer in capillary electrophoresis, the enantioselectivity and the mobility of analytes which interact with that chiral selector may be altered. The changes in enantioselectivity and mobility of the analyte are a function of the strength of the affinity interaction, which depends on the structure of each. The macrocyclic antibiotic vancomycin contains a variety of functionalities that are known to be useful for enantioselective interactions (e.g., hydrogen bonding groups, hydrophobic pockets, aromatic groups, amide linkages). Capillary electrophoresis with vancomycin as a buffer additive was used to separate the enantiomers of different compounds. In this study, the chiral separation of quinolonecarboxylic acids that exhibit marked antibacterial activity and of related compounds was achieved by capillary electrophoresis using vancomycin. The correlations between the separation parameters and analyte structures were investigated. The molecular interaction, which is based on the differences of structure, and the effect of experimental parameters on the enantioselective separation between the quinolonecarboxylic acids and vancomycin are discussed.

Anti-Infective Agents↗
PubMed1998

Separation of chiral compounds by capillary electrophoresis.

This review presents the different chiral selectors used in capillary electrophoresis (CE) for the separation of enantiomers. The use of charged cyclodextrins, crown ethers, polysaccharides, proteins, natural and synthetic micelles, macrocyclic antibiotics and ergot alkaloids is discussed in detail. Neutral native and derivatized cyclodextrins are not treated because several review articles have already been published on this topic. Recent developments like the application of two chiral selectors in the same background electrolyte are highlighted.

Electrophoresis, Capillary↗
PubMed1995

Differential requirement of protein tyrosine kinase and protein kinase C in the generation of IL-2-induced LAK cell and alpha CD3-induced CD3-AK cell responses.

This study examined the role of protein tyrosine kinase (PTK) and protein kinase C (PKC) in the signal transduction pathways for lymphocyte activation through IL-2R to generate LAK cells and through TCR-CD3 to generate CD3-AK cells. Two PTK inhibitors [herbimycin A and genistein (PTK-I)] and two PKC inhibitors [calphositin C and staurosporine (PKC-I)] were used in the experiments. It was found that the primary activation pathway through IL-2R was PTK-dependent; that is, generation of both the IL-2-induced proliferative and the cytotoxic responses was completely abrogated by PTK-I and not by PKC-I. Quite different results were obtained with the alpha CD3-induced CD3-AK cell response. First, the alpha CD3-induced proliferation was only partially inhibited by PTK-I or PKC-I alone. Second, generation of CD3-AK cytotoxic response was primarily PKC-dependent; that is, only PKC-I induced significant inhibition. Genistein was found to reduce protein tyrosine phosphorylation in both LAK cells and CD3-AK cells, indicating that CD3-AK cells were also susceptible to PTK-I treatment. Further studies showed that PTK-I and not PKC-I suppressed perforin mRNA expression and N-2-benzyoxycarbonyl-L-lysine thiobeneylester esterase production in LAK cells, and the opposite was true for CD3-AK cells. These results indicate that different pathways were employed in lymphocyte activation through IL-2R and TCR-CD3. The former pathway is primarily PTK-dependent. Activation through TCR-CD3 is a more complex event.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaloids↗
PubMed2001

Synthesis and biological activity of novel macrocyclic antifungals. modification of the tyrosine moiety of the lipopeptidolactone FR901469.

A series of tyrosine-modified derivatives of the macrocyclic lipopeptidolactone FR901469 have been prepared and evaluated for in vitro and in vivo antifungal activity and for hemolytic activity towards red blood cells. Compound 14 displayed significantly reduced hemolytic potential at 1mg/mL and a comparable protective effect to FR901469 in a mouse candidiasis model.

Animals↗
PubMed2000

Crystal structures and solution behavior of paramagnetic divalent transition metal complexes (Fe, Co) of the sterically encumbered tridentate macrocycles 1,4,7-R3-1,4,7-triazacyclononane: coordination numbers 5 (R = i-Pr) and 6 (R = i-Bu).

The coordination chemistry of the sterically hindered macrocyclic triamines, 1,4,7-R3-1,4,7-triazacyclononane (R = i-Pr, i-Pr3tacn, and R = i-Bu, i-Bu3tacn) with divalent transition metals has been investigated. These ligands form a series of stable novel complexes with the triflate salts MII(CF3SO3)2 (M = Fe, Co, or Zn) under anaerobic conditions. The complexes Fe(i-Pr3tacn)(CF3SO3)2 (2), [Co(i-Pr3tacn)(SO3CF3)(H2O)](CF3SO3) (3), [Co(i-Pr3tacn)(CH3CN)2](BPh4)2 (4), Zn(i-Pr3tacn)(CF3SO3)2 (5), [Fe(i-Bu3tacn)(CH3CN)2(CF3SO3)](CF3SO3) (6), Fe(i-Bu3tacn)-(H2O)(CF3SO3)2 (7), and Co(i-Bu3tacn)(CF3SO3)2 (8) have been isolated. The behavior of these paramagnetic complexes in solution is explored by their 1H NMR spectra. The solid-state structures of four complexes have been determined by X-ray single-crystal crystallography. Crystallographic parameters are as follows. 2: C17H33F6FeN3O6S2, monoclinic, P2(1)/n, a = 10.895(1) A, b = 14.669(1) A, c = 16.617(1) A, beta = 101.37(1) degrees, Z = 4. 3: C17H35CoF6N3O7S2, monoclinic, P2(1)/c, a = 8.669(2) A, b = 25.538(3) A, c = 12.4349(12) A, beta = 103.132(13) degrees, Z = 4. 6: C24H45F6FeN5O6S2, monoclinic, P2(1)/c, a = 12.953(6) A, b = 16.780(6) A, c = 15.790(5) A, beta = 96.32(2) degrees, Z = 4. 7: C20H41F6FeN3O7S2, monoclinic, C2/c, a = 22.990(2) A, b = 15.768(2) A, c = 17.564(2) A, beta = 107.65(1) degrees, Z = 8. The ligand i-Pr3tacn leads to complexes in which the metal ions are five-coordinate, while it's isobutyl homologue affords six-coordinate complexes. This difference in the stereochemistries around the metal center is attributed to steric interactions involving the bulky alkyl appendages of the macrocycles.

Cobalt↗
PubMed1996

Novel Redox-Active Cyclophanes Based on 3,3'-Biindolizines: Synthesis and Chirality.

The first compounds of a new series of redox-active cyclophanes were prepared by dehydrocyclization of bridged indolizines of type 1. The bridged dipyridino-compounds 2a and 2b obtained by reaction of 2 mol of lithiated alpha-picolines with dihalides were used as starting materials. Subsequent treatment of 2a,b with 2 mol of alpha-bromo ketones gave quaternary pyridinium halides. Ring closure in an alkaline medium (Chichibabin reaction) yielded the starting material for the synthesis of the macrocycles. Oxidative C-C coupling gave the diastereomeric cyclophanes of type 3. In all cases one pair of the enantiomers was obtained in excess. CV-investigations have shown that the main products are reversible redox systems. To clarify their conformations, compounds 3c, 3d/1, and3d/2 were subjected to X-ray analysis.

Journal Article↗
PubMed2002

Three novel cytochalasins X, Y, and Z from Pseudeurotium zonatum.

Fermentation of Pseudeurotium zonatum led to the isolation of the known cytochalasin G (1) and three new cytochalasins, X, Y, and Z (2-4). These four compounds are the only naturally occurring cytochalasins reported to date that contain an indole-substituted perhydroisoindol-1-one fused with an 11-membered macrocycle.

Ascomycota↗
PubMed2001

Solid-state supramolecular structures of resorcinol-arylboronic acid compounds.

[structure: see text] An X-ray crystallographic study of unique hydrogen-bonded supramolecular solid-state networks comprised of a tetraarylboronic acid resorcinarene is described. When 1 is recrystallized from 9:1 MeOH:EtOH, partial esterification takes place to give compound 2, the corresponding half methyl ester, which forms an infinite two-dimensional array. Each molecule participates in 12 hydrogen bonds with other macrocycles. These hydrogen bonds are both B-OH- - - OH (phenolic) and OH (phenolic)- - -OH (phenolic).

Boronic Acids↗
PubMed2003

Formal synthesis of (-)-apicularen A.

[reaction: see text] A formal synthesis of (-)-apicularen A has been completed. The synthesis features a cyanohydrin acetonide coupling as a convergent approach to the C9-C18 segment and an intramolecular Diels-Alder addition sequence to create both the 10-membered macrocycle and the aromatic ring.

Acetone↗
PubMed2005

Photodynamic inactivation of Escherichia coli by novel meso-substituted porphyrins by 4-(3-N,N,N-trimethylammoniumpropoxy)phenyl and 4-(trifluoromethyl)phenyl groups.

The photodynamic effect of novel cationic porphyrins, with different pattern of meso-substitution by 4-(3-N,N,N-trimethylammoniumpropoxy)phenyl (A) and 4-(trifluoromethyl)phenyl (B) groups, have been studied in both solution bearing photooxidizable substrates and in vitro on a typical Gram-negative bacterium Escherichia coli. In these sensitizers, the cationic groups are separated from the macrocycle ring by a propoxy spacer. Thus, the charges have a high mobility and a minimal influence on photophysical properties of the porphyrin. These compounds produce singlet molecular oxygen, O2(1Delta(g)), with quantum yields of approximately 0.41-0.53 in N,N-dimethylformamide. In methanol, the l-tryptophan photodecomposition increases with the number of cationic charges in the sensitizer. In vitro investigations show that cationic porphyrins are rapidly bound to E. coli cells in approximately 5 min. A higher binding was found for A3B3+ porphyrin, which is tightly bound to cells still after three washing steps. Photosensitized inactivation of E. coli cellular suspensions follows the order: A3B3+ > A44+>> ABAB2+ > AB3+. Under these conditions, a negligible effect was found for 5,10,15,20-tetra(4-sulfonatophenyl)porphyrin (TPPS4(4-)) that characterizes an anionic sensitizer. Also, the results obtained for these new cationic porphyrins were compared with those of 5,10,15,20-tetra(4-N,N,N-trimethylammonium phenyl)porphyrin (TTAP4+), which is a standard active sensitizer established to eradicate E. coli. The photodynamic activity of TTAP4+ is quite similar to that produced by A4(4+). Studies in an anoxic condition indicate that oxygen is necessary for the mechanism of action of photodynamic inactivation of bacteria. The higher photodynamic activity of A3B3+ was confirmed by growth delay experiments. Photodynamic inactivation capacities of these sensitizers were also evaluated in E. coli cells immobilized on agar surfaces. Under these conditions, A3B3+ porphyrin retains a high activity to inactivate localized bacterial cells. Therefore, tricationic porphyrin A3B3+ is an interesting sensitizer with potential applications in photodynamic inactivation of bacteria in liquid suspensions or on surfaces.

Benzene Derivatives↗
PubMed2006

A biochemical rationale for the anticancer effects of Hsp90 inhibitors: slow, tight binding inhibition by geldanamycin and its analogues.

Heat shock protein (Hsp)90 is emerging as an important therapeutic target for the treatment of cancer. Two analogues of the Hsp90 inhibitor geldanamycin are currently in clinical trials. Geldanamycin (GA) and its analogues have been reported to bind purified Hsp90 with low micromolar potency, in stark contrast to their low nanomolar antiproliferative activity in cell culture and their potent antitumor activity in animal models. Several models have been proposed to account for the approximately 100-fold-greater potency in cell culture, including that GA analogues bind with greater affinity to a five-protein Hsp90 complex than to Hsp90 alone. We have determined that GA and the fluorescent analogue BODIPY-GA (BDGA) both demonstrate slow, tight binding to purified Hsp90. BDGA, used to characterize the kinetics of ligand-Hsp90 interactions, was found to bind Hsp90alpha with k(off) = 2.5 x 10(-3) min(-1), t(1/2) = 4.6 h, and Ki* = 10 nM. It was found that BDGA binds to a functional multiprotein Hsp90 complex with kinetics and affinity identical to that of Hsp90 alone. Also, BDGA binds to Hsp90 from multiple cell lysates in a time-dependent manner with similar kinetics. Therefore, our results indicate that the high potency of GA in cell culture and in vivo can be accounted for by its time-dependent, tight binding to Hsp90 alone. In the broader context, these studies highlight the essentiality of detailed biochemical characterization of drug-target interactions for the effective translation of in vitro pharmacology to cellular and in vivo efficacy.

Animals↗
PubMed2000

3,6,9,16,19,22-Hexaazatricyclo

The adduct (1) formed between the hexaaza macrocycle 3,6,9,16,19,22-hexaazatricyclo[22.2.2.2(11,14]triconta-1(26),11(29),12,14(30),24,27-hexaene, C24H38N6, and 4,4'-sulfonyldiphenol, O2S(C6H4OH)2, is a salt [(C24H40N6)2+].2[(HOC6H4SO2C6H4O)-], and the adduct (2) formed by the same macrocyclic amine with 4,4'-biphenol is an aquated salt which also contains neutral biphenol molecules, [(C24H40N6)2+]. 2[(HOC6H4C6H4O)-].(HOC6H4C6H4OH).2H2O. In both compounds the cations lie across centres of inversion: there are two crystallographically distinct cation sites in (1) and the conformations of the cations occupying them are quite different. In (2) the single type of cation site is occupied by a conformationally disordered cation: the major and minor components represent two further distinct conformers. In (1) the anions are linked by O-H...O hydrogen bonds into chains, and each cation is linked by a total of six N-H...O hydrogen bonds to anions in four different chains, so linking the chains into continuous sheets. In (2) the anions and the water molecules are linked into sheets, which are further linked into a continuous three-dimensional framework by both the cations and the neutral biphenol units.

Journal Article↗