Design,synthesis, and biological evaluation of largazole derivatives: alteration of the zinc-binding domain

A new series of largazole analogues in which the side chain was replaced with disulfide groups were synthesized, and their biological activities were evaluated. Compound 8 bearing an octyl moiety showed much better selectivity for HDAC1 over HDAC7 than largazole (320-fold). Structure–activity relationships suggested that the length in the disulfide chain of largazole is important for the selectivity toward HDAC1 over HDAC7.     

Total synthesis and molecular target of largazole, a histone deacetylase inhibitor

Full details of the concise and convergent synthesis (eight steps, 19% overall yield), its extension to the preparation of a series of key analogues, and the molecular target and pharmacophore of largazole are described. Central to the synthesis of largazole is a macrocyclization reaction for formation of the strained 16-membered depsipeptide core followed by an olefin cross-metathesis reaction for installation of the thioester. The biological evaluation of largazole and its key analogues, including an acetyl analogue, a thiol analogue, and a hydroxyl analogue, suggested that histone deacetylases (HDACs) are molecular targets of largazole and largazole is a class I HDAC inhibitor. In addition, structure-activity relationship (SAR) studies revealed that the thiol group is the pharmacophore of the natural product. Largazole's HDAC inhibitory activity correlates with its antiproliferative activity.     

Total synthesis and biological mode of action of largazole: a potent class I histone deacetylase inhibitor

The efficient total synthesis of the recently described natural substance largazole (1) and its active metabolite largazole thiol (2) is described. The synthesis required eight linear steps and proceeded in 37% overall yield. It is demonstrated that largazole is a pro-drug that is activated by removal of the octanoyl residue from the 3-hydroxy-7-mercaptohept-4-enoic acid moiety to generate the active metabolite 2, which is an extraordinarily potent Class I histone deacetylase inhibitor. Synthetic largazole and 2 have been evaluated side-by-side with FK228 and SAHA for inhibition of HDACs 1, 2, 3, and 6. Largazole and largazole thiol were further assayed for cytotoxic activity against a panel of chemoresistant melanoma cell lines, and it was found that largazole is substantially more cytotoxic than largazole thiol; this difference is attributed to differences in the cell permeability of the two substances.     

Total syntheses of the histone deacetylase inhibitors largazole and 2-epi-largazole: application of N-heterocyclic carbene mediated acylations in complex molecule synthesis

Details of the evolution of strategies toward convergent assembly of the histone deacetylase inhibiting natural product largazole exploiting γ,δ-unsaturated-α,β-epoxy-aldehydes and a thiazole-thiazoline containing ω-amino-acid are described. The initial N-heterocyclic carbene mediated redox amidation exploying these two types of building blocks representing largazole's structural domains of distinct biosynthetic origin directly afforded the seco-acid of largazole. This was accomplished without any protecting groups resident upon either thioester bearing epoxy-aldehyde or the tetrapeptide. However, the ineffective production of largazole via the final macrolactonization led to an alternative intramolecular esterification/macrolactamization strategy employing the established two building blocks. This provided largazole along with its C2-epimer via an unexpected inversion of the α-stereocenter at the valine residue. The biological evaluation demonstrated that both largazole and 2-epi-largazole led to dose-dependent increases of acetylation of histone H3, indicating their potencies as class I histone deacetylase selective inhibitiors. Enhanced p21 expression was also induced by largazole and its C2 epimer. In addition, 2-epi-largazole displayed more potent activity than largazole in cell viability assays against PC-3 and LNCaP prostate cancer cell lines.     

Structural basis of the antiproliferative activity of largazole, a depsipeptide inhibitor of the histone deacetylases

Largazole is a macrocyclic depsipeptide originally isolated from the marine cyanobacterium Symploca sp., which is indigenous to the warm, blue-green waters of Key Largo, Florida (whence largazole derives its name). Largazole contains an unusual thiazoline-thiazole ring system that rigidifies its macrocyclic skeleton, and it also contains a lipophilic thioester side chain. Hydrolysis of the thioester in vivo yields largazole thiol, which exhibits remarkable antiproliferative effects and is believed to be the most potent inhibitor of the metal-dependent histone deacetylases (HDACs). Here, the 2.14 ?-resolution crystal structure of the HDAC8-largazole thiol complex is the first of an HDAC complexed with a macrocyclic inhibitor and reveals that ideal thiolate-zinc coordination geometry is the key chemical feature responsible for its exceptional affinity and biological activity. Notably, the core structure of largazole is conserved in romidepsin, a depsipeptide natural product formulated as the drug Istodax recently approved for cancer chemotherapy. Accordingly, the structure of the HDAC8-largazole thiol complex is the first to illustrate the mode of action of a new class of therapeutically important HDAC inhibitors.     

Largazole: from discovery to broad-spectrum therapy

The cyclic depsipeptide largazole from a cyanobacterium of the genus Symploca is a marine natural product with a novel chemical scaffold and potently inhibits class I histone deacetylases (HDACs). Largazole possesses highly differential growth-inhibitory activity, preferentially targeting transformed over non-transformed cells. The intriguing structure and biological activity of largazole have attracted strong interest from the synthetic chemistry community to establish synthetic routes to largazole and to investigate its potential as a cancer therapeutic. This Highlight surveys recent advances in this area with a focus on the discovery, synthesis, target identification, structure-activity relationships, HDAC8-largazole thiol crystal structure, and biological studies, including in vivo anticancer and osteogenic activities.     

Synthetic routes and biological evaluation of largazole and its analogues as potent histone deacetylase inhibitors

Natural products with interesting biological properties and structural diversity have often served as valuable lead drug candidates for the treatment of various human diseases. Largazole, isolated from the marine cyanobacterium Symploca sp. has exhibited potent inhibitory activity against many cancer cell lines. Besides, it shows remarkable selectivity between transformed and nontransformed cells, which is the main disadvantage of other antitumor natural products such as paclitaxel and actinomycin D. Due to its potential as a potent and selective anticancer drug candidate, a great deal of attention has been focused on largazole and its analogues. It is the aim of this review to highlight synthetic aspects of largazole and its analogues as well as their preliminary structure-activity relationship studies.     

Total synthesis of spiruchostatin B aided by an automated synthesizer

The total synthesis of a natural product HDAC inhibitor, spiruchostatin B, was successfully achieved. A 5-step synthesis that included an asymmetric aldol reaction was carried out in an automated synthesizer to provide an (E)-(S)-3-hydroxy-7-thio-4-heptenoic acid segment that is the crucial structure of cysteine-containing, depsipeptidic natural products such as spiruchostatins, FK228, FR901375, and largazole for their inhibitory activity against HDACs.     

Synthesis of the thiazole-thiazoline fragment of largazole analogues

The thiazole-thiazoline fragment of the marine natural product largazole, a potent histone deacetylase 1 inhibitor, has been synthesized in five steps. The methodology provides rapid access to thiazole-4-carbonitrile, thiazole-4-carbimidate, thiazole-oxazoline, and other thiazole-thiazoline derivatives that are important intermediates in the total synthesis of many natural products with important biological properties.     

Total Synthesis of (18S)‐ and (18R)‐Homolargazole by Rhodium‐Catalyzed Hydrocarboxylation

Homolargazole derivatives, in which the macrocycle of natural largazole is extended by one methylene group, were prepared by the recently developed rhodium‐catalyzed hydrocarboxylation reaction onto allenes. This strategy gives access to both the (18S)‐ and (18R)‐stereoisomers in high stereoselectivity under ligand control.     

Synthesis,structure, electrical properties,and band structure calculations of TiAsTe

The new compound TiAsTe has been synthesized by the reaction of the elements in a LiCl/KCl flux at 923 K. The compound crystallizes with four formula units in space group Immm of the orthorhombic system in a cell at 153 K of a = 3.5730(8) A, b = 5.249(1) A, c = 12.794(3) A, V = 240.0(1) A(3). The structure, which is of the NbPS structure type, is a three-dimensional extended framework built from bicapped TiAs(4)Te(4) trigonal prisms. It may be considered to comprise infinity (2) [TiTe] slabs perpendicular to [001] that are interspersed with linear infinity (1)[As] chains running along [010]. The As-As distances alternate at 2.554(2) and 2.695(2) A. Electrical and thermopower measurements indicate that TiAsTe is an n-type metallic compound. Density functional theory calculations help rationalize the chemical bonding and physical properties.     

Electronic spectroscopy of jet-cooled HCP+: molecular structure, phosphorus hyperfine structure, and Renner-Teller analysis

Laser-induced fluorescence spectra of jet-cooled HCP(+) and DCP(+) have been obtained with the pulsed discharge technique using HCPDCP and argon precursor mixtures. Transitions involving all of the excited state vibrations have been observed and a set of vibrational constants has been obtained. High-resolution spectra of the (2)Pi(32) components of the 0(0) (0) bands of both isotopomers have been recorded, and these spectra show resolved phosphorus hyperfine structure which allowed the determination of the excited state Fermi contact parameter. The B values were used to obtain the ground and excited state effective geometric parameters as r(0) (")(CH)=1.077(2) A, r(0) (")(CP)=1.6013(3) A, r(0) (')(CH)=1.082(2) A, and r(0) (')(CP)=1.5331(3) A. A Renner-Teller analysis of the ground state vibrational energy levels obtained from the literature was attempted. All of the observed levels of DCP(+) and the majority of those of HCP(+) were satisfactorily fitted with a standard Renner-Teller model, but three HCP(+) levels showed large systematic deviations which could not be accommodated by reassignments or improvements in the Fermi resonance Hamiltonian. Further improvements in the theory or in the experimental data will be needed to resolve this discrepancy.     

Synthesis, structure, and toxicity of arylgermatranes

A series of tolylgermatranes were synthesized. Their structures and the length of the transannular N→Ge bond were determined. It was shown that arylgermatranes are less toxic than the corresponding silatranes.     

Synthesis, structure, and preparative transamination of tetrazinc carbamato complexes having the basic zinc carboxylate structure

The series of tetranuclear zinc(II) carbamato complexes (Zn(4)O)(O(2)CR)(6), (1, R = diethylamino; 2, R = piperidino; 3, R = pyrrolidino) was prepared. Complexes 2 and 3 were crystallographically characterized and shown to have the same tetrahedral Zn(4)O(6+) core. Complex 2 crystallizes in the cubic space group I(-)43d, a = 24.0131(5) A, V = 13846.6(5) A(3), R(1976 observed reflections) = 0.0194, and GOF = 1.013. Complex 3 crystallizes in the triclinic space group P(-)1, a = 10.3178(6) A, b = 10.6962(6) A, c = 19.5130(11) A, alpha = 81.9070(10), beta = 75.4880(10), gamma = 81.6540(10), V = 2050.4(2) A(3), R(6141 observed reflections) = 0.0334, and GOF = 0.979. NMR spectroscopy was used to show that the (Zn(4)O)L(6) structure was maintained in nonpolar solvents. The complexes reacted with free amine in nonpolar solvents, which resulted in facile conversion of one member of the series to another. For example, reacting 1 with a stoichiometric amount of pyrrolidine in tetrahydrofuran followed by workup resulted in the quantitative formation of 3 with liberation of diethylamine. Formally, this is a transamination metathesis reaction between the diethylcarbamate ligand and pyrrolidine. The reaction is complete within 3 min at room temperature, in marked contrast to the extreme conditions required to effect transamination on organic carbamates. The complexes also undergo a facile transcarboxylation reaction with carbon dioxide which results in scrambling of the carboxyl group of the carbamate ligand with free CO(2), also complete in about 3 min. Both transamination and transcarboxylation reactions are consistent with the intermediacy of free CO(2). However, because of the propensity for the complexes to hydrolyze to liberate CO(2), the role of adventitious moisture in facilitating the reaction cannot presently be rejected.     

Cu4Mo6Se8: synthesis, crystal structure, and electronic structure of a new Chevrel phase structure type

Cu4Mo6Se8 has been synthesized by intercalation of Cu into Cu2Mo6Se8 at room temperature, and its crystal structure has been determined. This compound crystallizes in the triclinic space group P, with a = 6.7609(8) A, b = 6.8122(7) A, c = 7.9355(10) A, alpha = 70.739(4) degrees , beta = 72.669(4) degrees , gamma = 84.555(5) degrees , and Z = 1. Instead of residing in the voids between corners or edges of Mo6Se8 clusters as in the classic R Chevrel structure, the Cu atoms in Cu4Mo6Se8 fully occupy four sites between faces of two adjacent Mo6Se8 clusters. Thus, two of the six Mo atoms in each cluster do not have capping Se atoms from neighboring clusters. This represents a new triclinic structure type for Chevrel phases. In addition to the synthesis and crystal structure, we present and discuss results from electronic structure calculations using both extended Hückel and density functional theory. These calculations predict Cu4Mo6Se8 to be metallic. We also report results from Cu intercalation into Chevrel phase sulfides and tellurides. Preliminary experiments suggest that a telluride analogue of Cu4Mo6Se8 exists.     

Organocadmium aminoalcoholates: synthesis, structure, and materials chemistry

The novel methylcadmium aminoalkoxides MeCd(dmae) (Hdmae = dimethylaminoethanol), MeCd(bdmap) [Hbdmap = 1,3- bis-(dimethylamino)-propan-2-ol], and MeCd(tdmap) [tdmap = 1,3- bis(dimethylamino)-2-(dimethylaminomethyl)-propan-2-ol] have been synthesized and structurally characterized. MeCd(dmae) (1) forms a tetrameric heterocubane with a Cd4O4 core, while MeCd(bdmap) (2) is trimeric and MeCd(tdmap) (3) is a dimer. Only in the case of MeCd(dmae) are all the ligand donors fully utilized. In solution, MeCd(tdmap) undergoes a Schlenk equilibrium, with Me2Cd and Cd(tdmap)2 evident at 218 K. The structure and solution-state chemistry of Cd(tdmap)2 (5) have been independently studied and, in the solid-state, found to exist as a dimer whose coordination number at cadmium (CN = 6) is greater than in the organocadmium complexes (CN = 4, 5). MeCd(tdmap) has been used as a single-source precursor for CdO films by LPCVD with a glass substrate temperature of only 140 degrees C. Evidence is also presented for the formation of a heterometallic precursor, [(MeZn)(MeCd)(tdmap)2] (6), which has been used to deposit films of CdO mixed with ZnO by LPCVD at 140 degrees C. The structure of Me4Cd4(tdmap)2Cl2 (4), obtained serendipitously, is also included. Crystal data: 1, C20H52Cd4N4O4, FW 862.26, triclinic, P1, a = 11.47560(10), b = 13.55400(10), c = 21.5966(2) A, alpha = 99.7869(4), beta = 90.7476(4), gamma = 98.7823(4) degrees, V = 3268.82(5) A(3), Z = 4; 2, C27H67Cd3N6O3, FW 861.07, triclinic, P1, a = 11.4148(2), b =13.1886(2), c = 14.3139(3) A, alpha = 102.1962(10), beta = 108.3064(10), gamma = 100.8446(10) degrees, V = 1923.09(6) A(3), Z = 4; 3, C22H54Cd2N6O2, FW 659.51, monoclinic, P2(1)/n, a = 10.2912(1), b = 13.46930(1), c = 11.79130(1) A, beta = 112.8051(1) degrees, V = 1506.59(2) A(3), Z = 2; 4, C24H60Cd4Cl2N6O2, FW 985.28, monoclinic, P2(1)/c, a = 10.89780(10), b = 20.3529(2), c = 16.5317(2) A, beta = 94.8550(10) degrees, V = 3653.61(7) A(3), Z = 4; 5, C40H96Cd2N12O4, FW 1034.09, orthorhombic, P2(1)cn, a = 12.33290(10), b = 14.25060(10), c = 29.9003(2) A, V = 5255.01(7) A(3), Z = 4.     

Casein structure,self-assembly and gelation

The literature on recent studies of casein structure and function is reviewed. Where appropriate, we try to reconcile conflicting views on the issue of secondary structure in these proteins, steering a middle course where possible. A suggestion is put forward that a coarser view, treating the caseins as block copolymers may be sufficient to rationalise much of the behaviour of these proteins in self-association, adsorption and micellar assembly.     

A serendipitous synthesis of (+)-gregatin B, second structure revisions of the aspertetronins, gregatins, and graminin A, structure revision of the penicilliols

A (DHQN)(2)AQN-promoted asymmetric dihydroxylation (92% ee) of the allyl chloride derived from enynol (E)-13 and an 8-step sequence provided access to the hydroxyethylated furanone (R)-21. Oxidation with MnO(2) furnished 50% furanone (+)-(R)-2a and 2.7% isomeric furanone (+)-(R)-3a. (R)-2a possesses the accepted constitution of (+)-gregatin B but its spectra are different. Surprisingly, (+)-(R)-3a equals the natural product. Analogous structure reassignments are due for the gregatins A and C-E, the aspertetronins A-B, graminin A, and the penicilliols A and B.     

Crystal growth, structure, magnetic, and transport properties of TbRhIn5

Single crystals of TbRhIn5 were synthesized using the flux growth method. TbRhIn5 adopts the HoCoGa5 structure type and crystallizes in the space group P4/mmm, Z = 1. Lattice parameters are a = 4.6000(6) A, c = 7.4370(11) A, and V = 157.29(6) A3. Transport measurements show that TbRhIn5 is metallic (drho/dT > 0). A sharp antiferromagnetic transition is observed at T(N) = 48 K in the susceptibility data for TbRhIn5, which is highly anisotropic when the field is oriented along the c axis and a-b plane of the crystal and has an average effective moment of 9.72 muB/Tb3+.     

Synthesis, crystal structure, magnetic properties, and electronic structure of the new ternary vanadate CuMnVO4

A new magnetic oxide, CuMnVO4, was prepared, and its crystal structure was determined by single-crystal X-ray diffraction. The magnetic properties of CuMnVO4 were characterized by magnetic susceptibility and specific heat measurements, and the spin exchange interactions of CuMnVO4 were analyzed on the basis of spin-polarized electronic band structure calculations. CuMnVO4 contains MnO4 chains made up of edge-sharing MnO6 octahedra containing high-spin Mn2+ cations. Our work shows that CuMnVO4 undergoes a three-dimensional antiferromagnetic transition at approximately 20 K. Both the intrachain and interchain spin exchanges are antiferromagnetic, and the interchain spin exchange is not negligible compared to the intrachain spin exchange.