Cytotoxic half-sandwich rhodium(III) complexes: Polypyridyl ligand influence on their DNA binding properties and cellular uptake

The DNA binding of polypyridyl (pp) (η⁵-C₅Me₅)Rh^III complexes of the types [(η⁵-C₅Me₅)RhCl(pp)](CF₃SO₃) (2-6) (pp = bpy, phen, dpq, dppz, dppn), [(η⁵-C₅Me₅)Rh{(Me₂N)₂CS}(pp)](CF₃SO₃)₂ (7-9) (pp = dpq, dppz, dppn) and [(η⁵-C₅Me₅)Rh(L)(pp)](CF₃SO₃) (10) (L = C₆H₅S⁻) and (11) (L = C₁₀H₇S⁻) has been studied by UV/Vis spectroscopy, circular dichroismus and viscosity measurements. Complexes 3-11 are cytotoxic towards the human MCF-7 breast and HT-29 colon cancer cell lines and exhibit IC₅₀ values in the range 0.56-10.7 μM. Stable intercalative binding into CT-DNA is indicated for the dpq and dppz complexes by large increases ΔT_m of 6-12 °C in the DNA thermal denaturation temperature for r = [complex]/[DNA] = 0.1 and by induced CD bands and large viscosity increases. In contrast, significant DNA lengthening is not observed after incubation of the biopolymer with the dppn complexes 2 and 9 at molar ratios of r < 0.08. Pronounced hypochromic shifts for the π-π^∗ transitions of the dppn ligands in the range 320-425 nm indicate the possible presence of surface stacking. The in vitro cytotoxicities of the chloro complexes 4-6 and the (Me₂N)₂CS complexes 7-9 are dependent on the size of the polypyridyl ligand with IC₅₀ values decreasing in the order dpq > dppz > dppn. For instance, IC₅₀ values of 5.3, 1.5 and 0.91 μM were determined for 7-9 against MCF-7 cells. Rapid Cl⁻/H₂O exchange leads the formation of aqua dications for 4-6, whose levels of cellular uptake and cytotoxicities are similar to those established for 7-9. Intramolecular interactions between the aromatic thiolate and dppz ligands of 10 and 11 prevent significant DNA intercalation. X-ray structural determinations have been performed for 2-7 and 11.     

DNA photocleavage and anticancer activity of terpyridine copper(II) complexes having phenanthroline bases

Copper(II) complexes [Cu(ph-tpy)(B)](ClO₄) (1–3), where ph-tpy is (4′-phenyl)-2,2′:6′,2″-terpyridine and B is N,N-donor phenanthroline base, viz. 1,10-phenanthroline (phen, 1), dipyridoquinoxaline (dpq, 2), and dipyridophenazine (dppz, 3), were prepared and characterized from analytical and spectral data. Complex 1, characterized by X-ray crystallography, shows a distorted square-pyramidal (4 + 1) CuN₅ coordination geometry having the tridentate ph-tpy ligand at the basal plane and bidentate phen bound to the axial-equatorial sites. The complexes display a d–d band near 650 nm in aqueous DMF. The complexes are avid binders to calf thymus DNA giving the binding order: 3 (dppz) > 2 (dpq) > 1 (phen). The dpq and dppz complexes show photo-induced DNA cleavage activity in red light via photo-redox pathway forming hydroxyl radicals. The cytotoxicity of the dppz complex 3 was studied by MTT assay in HeLa cancer cells. The IC₅₀ values are 3.7 and 12.4 μM in visible light of 400–700 nm and dark, respectively.     

Photocytotoxic and anaerobic DNA cleavage activity of binuclear 3,3′-dithiodipropionic acid cobalt(II) complexes having phenanthroline bases

Dicobalt(II) complexes [{(B)Co^II}₂(μ-dtdp)₂] (1–3) of 3,3′-dithiodipropionic acid (dtdp) and phenanthroline bases (B), viz. 1,10-phenanthroline (phen in 1), dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq in 2) and dipyrido[3,2-a:2′,3′-c]phenazine (dppz in 3), have been prepared, characterized and their photo-induced anaerobic DNA cleavage activity studied. The elemental analysis and mass spectral data suggest binuclear formulation of the complexes. The redox inactive complexes have magnetically non-interacting dicobalt(II) core showing magnetic moment of ∼3.9 μ_B per cobalt(II) center. The complexes show good binding propensity to calf thymus DNA giving K_b values within 4.3 × 10⁵–4.0 × 10⁶ M⁻¹. Thermal melting and viscosity data predict DNA groove binding and/or partial intercalative nature of the complexes. The complexes show significant anaerobic DNA cleavage activity in green light under argon atmosphere possibly involving radical species generated from the disulfide moiety in a type-I pathway. The DNA cleavage reaction under aerobic medium in green light is found to involve hydroxyl radical species. The dppz complex 3 exhibits significant photocytotoxicity in HeLa cervical cancer cells with an IC₅₀ value of 2.3 μM in UV-A light of 365 nm, while it is essentially non-toxic in dark giving an IC₅₀ value of >200 μM. A significant reduction of the dark toxicity of the organic dppz base (IC₅₀ = 8.3 μM in dark) is observed on binding to the cobalt(II) center while essentially retaining its photocytotoxicity in UV-A light (IC₅₀ = 0.4 μM).     

Anticancer drugs based on alkenyl and boryl substituted titanocene complexes

The alkenyl-substituted titanocene complex [Ti(η⁵-C₅H₅)(η⁵-C₅H₄{CMe₂(CH₂CH₂CHCH₂)})Cl₂] (1) has been synthesized and characterized using traditional methods. The reaction of 1 with 9-BBN gave the boryl substituted complex [Ti(η⁵-C₅H₅)(η⁵-C₅H₄{CMe₂(CH₂CH₂CH₂CH₂BC₈H₁₄)})Cl₂] (2). The cytotoxic activity of 1 and 2 was tested against tumour cell lines human adenocarcinoma HeLa, human myelogenous leukemia K562, human malignant melanoma Fem-x, human breast carcinoma MDA-MB-361 and normal immunocompetent cells peripheral blood mononuclear cells PBMC and compared with those of the reference complexes [Ti(η⁵-C₅H₅)₂Cl₂] (R1), [Ti(η⁵-C₅H₄Me)₂Cl₂] (R2) and [Ti(η⁵-C₅H₅)(η⁵-C₅H₄SiMe₃)Cl₂] (R3). Complex 1 showed higher cytotoxic activities on HeLa, Fem-x and K562 (IC₅₀ values from 96.6 ± 3.4 to 149.2 ± 2.9 μM) than the reference complexes R1, R2 and R3 which presented IC₅₀ values from 173.3 ± 6.0 to >200 μM. On the other hand, boryl substituted complex 2, present slightly lower cytotoxic activities than 1 on HeLa, Fem-x and K562 (IC₅₀ values from 155.6 ± 5.5 to 167.9 ± 4.2 μM). However, 2 was the most active of the studied complexes against MDA-MB-361 (IC₅₀ value of 161.1 ± 0.1 μM). Structural studies based on DFT calculations of 1 and 2 have also been carried out in order to gain a possible insight into the relationship between metal complex structure and cytotoxicity.     

Orthopalladation of phosphorus ylides in endo position with bidentate ligands

The ortho-metallated complexes [Pd₂{κ²(C,C)-C₆H₄(PPh₂CHC(O)C₆H₅R}₂(μ-Cl)₂] (R = Ph (1a), NO₂ (1b), Br (1c)) were prepared by refluxing equimolar mixtures of Ph₃PCHC(O)C₆H₅R, (R = Ph, NO₂, Br) and Pd(OAc)₂ in MeOH, followed by an excess of NaCl. The dinuclear complexes (1a-1c) react with silver trifluoromethylsulfonate and bidentate ligands [L = bipy (2,2′-bipyridine), phen (phenanthroline), dppe (bis(diphenylphosphino)ethane), dppp (bis(diphenylphosphino)propane)] giving the mononuclear stabilized orthopalladated complexes in endo position [Pd{κ²(C,C)-C₆H₄(PPh₂CHC(O)R}L](OTf) [R = Ph, L = phen (2a), bipy (3a), dppe (4a), dppp (5a); R = NO₂, L = phen (2b), bipy (3b), dppe (4b), dppp (5b); R = Br, L = phen (2c), bipy (3c), dppe (4c), dppp (5c); OTf = trifluoromethylsulfonate anion]. Orthometalation and ylidic C-coordination are demonstrated by an X-ray diffraction study of 2c and 3c. In the structures, the palladium atom shows a slightly distorted square-planar coordination geometry.     

Fascioquinols A-F: bioactive meroterpenes from a deep-water southern Australian marine sponge, Fasciospongia sp.

Chemical investigation of a southern Australian deep-water marine sponge, Fasciospongia sp., returned the new meroterpene sulfate fascioquinol A (1) together with a series of acid mediated hydrolysis/cyclization products, fascioquinols B (2), C (3) and D (4), and strongylophorine-22 (5). Additional co-metabolites include the new meroterpenes fascioquinol E (6) and fascioquinol F (8), together with the known sponge metabolite geranylgeranyl 1,4-hydroquinone (7). Structures were assigned to 1-8 on the basis of detailed spectroscopic analysis, chemical interconversion, mechanistic and biosynthetic considerations, and literature comparisons. The known 1,4-hydroquinone 7 was identified as the dominant cytotoxic principle in the Fasciospongia sp. extract, with selective inhibitory activity against gastric adenocarcinoma (AGS, IC₅₀ 8 μM) and neuroblastoma (SH-SY5Y, IC₅₀ 4 μM) cell lines. By contrast, while the fascioquinols displayed little or no inhibitory activity towards human cell lines, 1 and 2 displayed promising Gram-positive selective antibacterial activity towards Staphylococcus aureus (IC₅₀ 0.9-2.5 μM) and Bacillus subtilis (IC₅₀ 0.3-7.0 μM).     

The synthesis, structural characterization and in vitro anti-cancer activity of novel N-(3-ferrocenyl-2-naphthoyl) dipeptide ethyl esters and novel N-(6-ferrocenyl-2-naphthoyl) dipeptide ethyl esters

N-(3-ferrocenyl-2-naphthoyl) dipeptide esters (5-7) and N-(6-ferrocenyl-2-naphthoyl) dipeptide esters (8-10) were prepared by coupling either 3-ferrocenylnaphthalene-2-carboxylic acid 2 or 6-ferrocenylnaphthalene-2-carboxylic acid 4 to the dipeptide ethyl esters GlyAla(OEt) (5, 8), AlaGly(OEt) (6, 9), and AlaAla(OEt) (7, 10) using the standard N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt) protocol. All the compounds were fully characterized using a combination of ¹H NMR, ¹³C NMR, DEPT-135 and ¹H-¹³C COSY (HMQC) spectroscopy, electrospray ionization mass spectrometry (ESI-MS) and cyclic voltammetry (CV). In vitro, the cytotoxic effects of compounds 5-10 show improvements over the corresponding N-(ferrocenyl)benzoyl derivatives, with IC₅₀ values against the H1299 lung cancer cells ranging from 1.2 μM to 8.0 μM. N-(6-ferrocenyl-2-naphthoyl)-glycine-l-alanine ethyl ester 8 was found to be the most active derivative of the naphthoyl series so far, displaying an IC₅₀ value of 1.3 ± 0.1 μM. This value is slightly lower than that found for the clinically employed anti-cancer drug cisplatin (IC₅₀ = 1.5 ± 0.1 μM against H1299).     

Synthesis and biological evaluation of analogs of altohyrtin C (spongistatin 2)

Several structural analogs that contain only part of the altohyrtin structure have been prepared and compared with synthetic altohyrtin C (2) for in vitro cytotoxicity against human colon (HCT116) and ovarian (A2780) cell lines. Whereas altohyrtin C was found to be exceedingly potent against these lines (IC₅₀=0.0003 μM), analogs 3-5 were >27,000-fold less potent (IC₅₀>8 μM). Analogs 6 and 7 also demonstrated weak cytotoxicity with IC₅₀ values for the HCT116 and A2780 cells of 4.8 μM and 2.4 μM, respectively, for 6.     

Rhenium and technetium tricarbonyl complexes anchored by 5-HT1A receptor-binding ligands containing P,O/N donor atom sets

The (2-methoxyphenyl)piperazine pharmacophore, a part of the WAY 100635 structure, has been functionalized with phosphinoarylbenzylamide or phosphinoarylbenzylamine chelator groups using propylene or hexylene alkyl chains as linkers (L2-L4). These heterofunctionalized phosphines bearing an arylpiperazine moiety have been used to stabilize rhenium tricarbonyl complexes of the type [Re(CO)₃Br(κ²-L)] (4, L = L2; 5, L = L3; 6, L = L4), which have been fully characterized, including by X-ray crystallographic analysis in the case of compounds 4 and 5. These monomeric complexes are six-coordinate, displaying a distorted octahedral coordination geometry with a facial arrangement of the carbonyl groups. The other three remaining positions are occupied by a bromide and by the bidentate heterofunctionalized phosphine, which coordinates through the phosphorus and the oxygen atom or through the phosphorus and the nitrogen atom in 4 and 5, respectively. The ^99mTc complexes (3a-6a) were also prepared and their characterization established by comparative HPLC, using the Re complexes as surrogates. The in vitro binding affinity for the 5HT_1A receptor subtype and the selectivity against the 5HT_2A receptors for the rhenium complexes were determined. Compound 3 is the only one which presents a reasonable affinity and selectively towards 5HT_1A (IC₅₀ = 20 nM) and 5HT_2A (IC₅₀ = 4680 nM) receptors, respectively. When the spacer length between the chelate unit and receptor binding domain increased and/or the amide group in the chelator was replaced by a secondary amine unacceptable affinity values for 5HT_1A receptors (IC₅₀ = 200-1100 nM) and lost of selectivity were observed.     

Synthesis and cytotoxicity studies of new dimethylamino-functionalised and heteroaryl-substituted titanocene anti-cancer drugs

From the carbolithiation of N,N-dimethylamino fulvene (3a) and different ortho-lithiated heterocycles (furan, thiophene and N-methylpyrrole), the corresponding lithium cyclopentadienide intermediate (4a-c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl₄ resulting in dimethylamino-functionalised titanocenes 5a-c. When these titanocenes were tested against LLC-PK cells, the IC₅₀ values obtained were of 240, and 28 μM for titanocenes 5a and 5b, respectively. The most cytotoxic titanocene 5c with an IC₅₀ value of 5.5 μM is found to be almost as cytotoxic as cis-platin, which showed an IC₅₀ value of 3.3 μM, when tested on the LLC-PK cell line, and titanocene 5c is approximately 400 times better than titanocene dichloride itself.     

Cationic arene ruthenium complexes containing chelating 1,10-phenanthroline ligands

The monocationic chloro complexes containing chelating 1,10-phenanthroline (phen) ligands [(arene)Ru(N∩N)Cl]⁺ (1: arene = C₆H₆, N∩N = phen; 2: arene = C₆H₆, N∩N = 5-NO₂-phen; 3: arene = p-MeC₆H₄Prⁱ, N∩N = phen; 4: arene = p-MeC₆H₄Prⁱ, N∩N = 5-NO₂-phen; 5: arene = C₆Me₆, N∩N = phen; 6: arene = C₆Me₆, N∩N = 5-NO₂-phen; 7: arene = C₆Me₆, N∩N = 5-NH₂-phen) have been prepared and characterised as the chloride salts. Hydrolysis of these chloro complexes in aqueous solution gave, upon precipitation of silver chloride, the corresponding dicationic aqua complexes [(arene)Ru(N∩N)(OH₂)]²⁺ (8: arene = C₆H₆, N∩N = phen; 9: arene = C₆H₆, N∩N = 5-NO₂-phen; 10: arene = p-MeC₆H₄Prⁱ, N∩N = phen; 11: arene = p-MeC₆H₄Prⁱ, N∩N = 5-NO₂-phen; 12: arene = C₆Me₆, N∩N = phen; 13: arene = C₆Me₆, N∩N = 5-NO₂-phen; 14: arene = C₆Me₆, N∩N = 5-NH₂-phen), which have been isolated and characterised as the tetrafluoroborate salts. The catalytic potential of the aqua complexes 8-14 for transfer hydrogenation reactions in aqueous solution has been studied: complexes 12 and 14 catalyse the reaction of acetophenone with formic acid to give phenylethanol and carbon dioxide with turnover numbers around 200 (80 °C, 7 h). In the case of 12, it was possible to observe the postulated hydrido complex [(C₆Me₆)Ru(phen)H]⁺ (15) in the reaction with sodium borohydride; 15 has been characterised as the tetrafluoroborate salt, the isolated product [15]BF₄, however, being impure. The molecular structures of [(C₆Me₆)Ru(phen)Cl]⁺ (1) and [(C₆Me₆)Ru(phen)(OH₂)]²⁺ (12) have been determined by single-crystal X-ray structure analysis of [1]Cl and [12](BF₄)₂.     

Novel octahedral nickel(II) dithiocarbamates with bi- or tetradentate N-donor ligands: X-ray structures of [Ni(Bzppzdtc)(phen)2]ClO4 · CHCl3 and [Ni(Bz2dtc)2(cyclam)]

A series of novel octahedral nickel(II) dithiocarbamate complexes involving bidentate nitrogen-donor ligands (phen = 1,10-phenanthroline, bpy = 2,2′-bipyridine) or a tetradentate ligand (cyclam = 1,4,8,11-tetraazacycloteradecane) of the composition [Ni(BzMetdtc)(phen)₂]ClO₄ (1), [Ni(Pe₂dtc)(phen)₂]ClO₄ (2), [Ni(Bzppzdtc)(phen)₂]ClO₄ · CHCl₃ (3), [Ni(Bzppzdtc)(phen)₂](SCN) (4), [Ni(BzMetdtc)(bpy)₂]ClO₄ · 2H₂O (5), [Ni(Pe₂dtc)(cyclam)]ClO₄ (6), [Ni(BzMetdtc)₂(cyclam)] (7), [Ni(Bz₂dtc)₂(cyclam)] (8) and [Ni(Bz₂dtc)₂(phen)] (9) (BzMetdtc = N,N-benzyl-methyldithiocarbamate(1-) anion, Pe₂dtc = N,N-dipentyldithiocarbamate(1-) anion, Bz₂dtc = N,N-dibenzyldithiocarbamate(1-) anion, Bzppzdtc = 4-benzylpiperazinedithiocarbamate(1-) anion), have been synthesized. Spectroscopic (electronic and infrared), magnetic moment and molar conductivity data, and thermal behaviour of the complexes are discussed. Single crystal X-ray analysis of 3 and 8 confirmed a distorted octahedral arrangement in the vicinity of the nickel atom with a N₄S₂ donor set. They represent the first X-ray structures of such type complexes. The catalytic influence of complexes 2, 3, 6, and 7 on graphite oxidation was studied and discussed.     

Bistabercarpamines A and B,first vobasinyl-chippiine-type bisindole alkaloid from Tabernaemontana corymbosa

Two novel dimeric monoterpene indole alkaloids, bistabercarpamines A (1) and B (2) possessing unprecedented bis-vobasinyl-chippiine-type skeleton, were isolated from the leaves of Tabernaemontana corymbosa. The structures were elucidated on the basis of spectroscopic data, and the absolute configurations of these isolates were determined by CD excition chirality method. Bistabercarpamine A (1) exhibited moderate cell growth inhibitory activity against HepG-2 cells with IC₅₀ of 38.14 ± 1.1 μM.     

Syntheses,supramolecular structures and properties of six coordination complexes based on 5-sulfosalicylic acid and bipyridyl-like chelates

Six new complexes constructed by 5-sulfosalicylic acid and bipyridyl-like ligands (2,2′-bipy and 1,10-phen), namely [Cu₄(OH)₂(ssal)₂(phen)₄ · 7H₂O] (1), [Cu₄(OH)₂(ssal)₂(bipy)₄ · 2H₂O] (2), [Cd(Hssal)(bipy)] (3), [Cd(HL)₂(phen)₂] (4), [Cr(ssal)(bipy)(H₂O)₂ · 2H₂O] (5) and [Cr(ssal)(phen)₂] (6) (H₃ssal = 5-sulfosalicylic acid, H₂L = p-hydroxybenzenesulfonic acid, bipy = 2,2′-bipy, phen = 1,10-phen) were prepared under hydrothermal conditions and their structures were determined by single-crystal X-ray diffraction. Complexes 1 and 2 are both tetranuclear copper complexes with a stepped topology. In complex 3, a new coordination mode of the Hssal²⁻ group is reported in this work. During the synthetic process of complex 4, in situ decarboxylation of 5-sulfosalicylic acid into p-hydroxybenzenesulfonic acid is involved. Two chromium 5-sulfosalicylates (5 and 6) are reported for the first time. These new complexes display different supramolecular structures by O–H?O, C–H?O hydrogen bonds as well as π?π, C–H?π and O?π interactions. The results of magnetic determination show that ferromagnetic interactions exist in complex 1, however, antiferromagnetic interactions exist in 2.     

Synthesis and structural characterisation of five copper(I) and silver(I) complexes with 2-aminopyridine (2-APy), [Cu(μ-Cl)(2-Apy)(PPh3)]2, [Ag(μ-X)(2-Apy)(PPh3)]2 (X = Cl,Br), [Ag(μ-ONO2)(2-Apy)(EPh3)]2 (E = P,As)

Five new copper(I)/silver(I) complexes containing 2-aminopyridine, [Cu(μ-Cl)(2-Apy)(PPh₃)]₂(1), [Ag(μ-Cl)(2-Apy)(PPh₃)]₂(2), [Ag(μ-Br)(2-Apy)PPh₃)]₂(3), [Ag(μ-ONO₂)(2-Apy)(PPh₃)]₂(4), [Ag(μ-ONO₂)(2-Apy)(AsPh₃)]₂(5) have been synthesised for the first time. Complexes 1–5 are obtained by the reactions of MX (MX = CuCl for 1; M = Ag for 2–5; X = Cl, Br for 2–3; X = NO₃ for 4–5) with the monodentate ligands EPh₃ (E = P for 1–4; E = As for 5) and 2-Apy in the molar ratio of 1:1:2 in the mixed solvent of CH₂Cl₂ and MeOH. Complexes 1–5 are characterised by IR and X-ray diffraction. In 1–5, chloride, bromide and nitrate ions bridge two metal atoms to form dinuclear complexes containing the parallelogram cores M₂X₂ (M = Cu, Ag).     

Labdanecaryophyllic acid, a novel cytotoxic C35 terpenoid from Calocedrus macrolepis var. formosana

Chemical investigation of the bark of Calocedrus macrolepis var. formosana, an endemic tree in Taiwan, has led to the isolation of a novel terpenoid 1. Compound 1 with a rare C₃₅ skeleton constructed by a diterpene and a sesquiterpene moieties. Its structure was elucidated by spectroscopic interpretations. The anti-proliferation activity of 1 against human oral epidermoid carcinoma KB cells was evaluated, and the IC₅₀ value was determined to be 9.2 ± 0.4 μM.     

Organometallic diphenols: The importance of the organometallic moiety on the expression of a cytotoxic effect on breast cancer cells

We have recently reported that the ferrocenyl diphenol compound 1,1-di(4-hydroxyphenyl)-2-ferrocenyl-but-1-ene 1 exhibited strong in vitro anti-proliferative effects on both hormone dependent (MCF7, IC₅₀ = 0.7 μM) and hormone independent (MDA-MB231, IC₅₀ = 0.6 μM) breast cancer cells. In order to assess the importance of the ferrocenyl motif, we have prepared a series of analogs using the organometallic fragments (η⁵-C₅H₄)Cp^∗Fe (7), ((η⁵-C₅H₄)(CH₃)₂phospholyl)Fe (9), (η⁵-C₅H₄)CpRu (10), (η⁵-C₅H₄)Re(CO)₃ (11), and (η⁵-C₅H₄)Mn(CO)₃ (12), and the chlorinated ferrocenyl derivative 1,1-di(4-hydroxyphenyl)-2-ferrocenyl-4-chloro-but-1-ene (4). The nature of the organometallic moiety had a strong influence on estrogen receptor alpha (ERα) recognition, with relative binding affinity (RBA) values ranging from 0.55% to 10.8%. The second isoform of the estrogen receptor, ERβ, was better able to accommodate these compounds, with RBA values ranging from 8.9% to 17.1%. Molecular modeling studies suggest that the orientation of the compounds and their interactions with the residues of ERα and ERβ binding sites are very similar. A study on the MCF7 hormone dependent breast cancer cell line revealed an anti-proliferative effect for the ferrocenyl phenols 1 and 4, while the other compounds displayed either a proliferative effect (9-12), or no effect (7). The anti-proliferative effect of 1 and 4 is also evident in the MDA-MB231 hormone independent breast cancer cell line (IC₅₀(4) = 1 μM), and can be attributed to the cytotoxicity of these compounds, while the other compounds showed no effect on this cell line. The cytotoxicity of 1 and 4 may arise from electron delocalization in the radical cation in alkaline conditions, possibly resulting in a cytotoxic quinone methide formation, while the other complexes do not undergo the formation of this entity, as evidenced by the electrochemical results.     

Malbrancheamide, a new calmodulin inhibitor from the fungus Malbranchea aurantiaca

Bioassay-directed fractionation of an ethyl acetate extract (mycelia and broth) of the fungus Malbranchea aurantiaca led to the isolation of the novel phytotoxic alkaloid (5aS,12aS,13aS)-8,9-dichloro-12,12-dimethyl-2,3,11,12,12a,13-hexahydro-1H,6H-5a,13a (epiminomethano)indolizino[7,6b]carbazol-14-one (1) of the brevianamide series. The phytotoxin was given the trivial name of malbrancheamide (1). The structure of 1 was unequivocally established by UV, NMR, MS and X-ray studies. The absolute configuration was established by X-ray analysis according to the method of Flack. According to the conformational studies using molecular mechanics analyses, 1 exists in one preferred conformation, which was optimized by DFT calculations. Compound 1 caused moderate inhibition of radicle growth of Amaranthus hypochondriacus (IC₅₀=0.37 μM) and inhibited the activation of the calmodulin-dependent enzyme PDE1 (IC₅₀=3.65±0.74 μM). This effect was comparable to that of chlorpromazine (IC₅₀=2.75±0.87 μM) a well characterized CaM antagonist. The inhibition mechanism of 1 was competitive with respect to CaM according to a kinetic analysis.     

Polyketides from the mangrove-derived endophytic fungus Acremonium strictum

Five new polyketide derivatives, 6′-hydroxypestalotiopsone C (1), acropyrone (2), bicytosporone D (3), waol acid (4), and pestalotiopene C (5), together with seven known metabolites (6–12), were obtained from extracts of the endophytic fungus Acremonium strictum, isolated from the mangrove tree Rhizophora apiculata. The structures of the isolated compounds were elucidated on the basis of comprehensive NMR and MS analysis. Compounds 6, 7, and 9 showed moderate cytotoxic activity against human cisplatin-sensitive (IC₅₀ values 27.1, 76.2, and 8.3 μM, respectively) and resistant A2780 cell lines (IC₅₀ values 12.6, 30.1, and 19.0 μM, respectively), whereas only 9 exhibited antibacterial activity against Staphylococcus aureus (MIC value 14.3 μM).