Novel titanocene anti-cancer drugs derived from fulvenes and titanium dichloride

Starting from 6-(p−N,N-dimethylanilinyl)fulvene (1a) or 6-(pentamethylphenyl)fulvene (1b) [1,2-di(cyclopentadienyl)-1,2-di(p−N,N-dimethylaminophenyl)ethanediyl] titanium dichloride (2a) and [1,2-di(cyclopentadienyl)-1,2-bis(pentamethylphenyl)ethanediyl] titanium dichloride (2b) and their corresponding dithiocyanato complexes (3a, 3b) were synthesized. Titanocene 2b did not show a cytotoxic effect, but when 2a was tested against pig kidney carcinoma cells (LLC-PK) or human ovarian carcinoma cells (A2780/cp70) inhibitory concentrations (IC₅₀) of 2.7 × 10⁻⁴ and 1.9 ×  10⁻⁴ M, respectively, were observed.     

Diels-Alder reaction of fulvenes with N-(3,5-dichlorophenyl)-maleimide

Summary N-(3,5-Dichlorophenyl)-maleimide reacts smoothly with a variety of substituted fulvenes (1) to give onlyendo adducts (3) independent of the nature of fulvene substituent,Lewis acid catalyst, and reaction solvent and temperature. The structure of theDiels-Alder adduct3f was determined by X-ray crystallography. Semi-empirical quantum methods (AM1) were used to rationalize theendo stereoselectivity.Dedicated to Professor Fritz Sauter on the occasion of his 65^th birthday     

Synthesis and thermal properties of a new styryl-functionalized pentafulvene glassy carbon precursor

The first preparation of a styryl-functionalized aryl pentafulvene 4 was carried out. In the crystal structure of 4, the packing of fulvene molecules results in the shortest intermolecular contacts between aligned vinyl groups. Thermal reactivity studies of 4 (DSC and TGA, under N₂) revealed a small difference between the melting point (120 °C) and the T_onset for cross-linking (125 °C), and provided strong evidence for the production of a network material (net4) due to reactivity of the attached styryl group. Pyrolysis of net4 under N₂ gave a glassy carbon product in low yield as revealed by powder X-ray and TGA analyses (carbon yield (TGA) of 38% (900 °C)).     

Benzyl-substituted titanocene dichloride anticancer drugs: From lead to hit

Through the reaction of Super Hydride (LiBEt₃H) with 6-phenyl-substituted fulvenes followed by transmetallation to TiCl₄ ten novel benzyl-substituted titanocene dichloride derivatives were synthesised. 6(4-morpholinomethyl-phenyl) fulvene (6g) and (bis-[(4-methoxymethyl-benzyl)cyclopentadienyl]titanium(IV) dichloride) (8a) were characterised by single crystal X-ray diffraction. All of the titanocenes had their cytotoxicity investigated through preliminary in vitro testing on the LLC-PK (pig kidney epithelial) cell line and CAKI-1 human kidney cell human carcinoma cell line in an MTT based assay in order to determine their IC50 values. The titanocenes synthesised were found to have IC50 values ranging from 2.3 (±0.3) μM (comparable to cisplatin) to others which show no anti-proliferative activity on this cell line in standard DMSO formulations on LLC-PK cell line. Eight of the titanocenes were found to be completely water-soluble and had IC50 values of 6.5 (±0.7) μM to no activity when using medium only for formulation. On the CAKI-1 cell line, IC50 values of 7.8 (±1.4) μM to no activity were found using DMSO formulation, while IC50 values of 0.55 (±0.32) μM to no activity were measured using just medium as the formulation reagent. Some of the titanocenes show significant cytotoxicity improvement when compared directly to the lead compound Titanocene Y (bis-[(p-methoxybenzyl)cyclopentadienyl] titanium(IV) dichloride) and are more cytotoxic than cisplatin. Bis-[(4-diethylaminomethyl-benzyl)cyclopentadienyl]titanium(IV) dichloride (8d) at this preliminary stage seems to be the most promising of the ten compounds prepared and exhibits nanomolar activity against CAKI-1.     

Synthesis and characterization of chromium(I) bis(η-toluene) derivatives containing sterically demanding anions

The reaction of Cr(η⁶-CH₃C₆H₅)₂ with 1-benzoyl-6-hydroxy-6-phenyl fulvene, dbcpH, and with pentakis(methoxycarbonyl)cyclopentadiene, pcmcpH, proceeds with evolution of dihydrogen and the formation of the ionic derivatives [Cr(η⁶-CH₃C₆H₅)₂][X] ([X]⁻ = 1,2-dibenzoylcyclopentadienyl, [dbcp]⁻, pentakis(methoxycarbonyl)cyclopentadienyl, [pcmcp]⁻), which have been characterized by IR and EPR spectroscopies, X-ray diffraction and electrochemical techniques. The sterically demanding anions do not affect the structural and electronic properties of the cations in solution but strongly influence crystal packing. In fact, a rare cis-eclipsed conformation of the toluene rings is found for [Cr(η⁶-CH₃C₆H₅)₂][dbcp] · THF, whereas two independent complexes are observed in the unit cell of [Cr(η⁶-CH₃C₆H₅)₂][pcmcp], one with toluene rings in a cis-eclipsed conformation and the other in a staggered conformation (projections of methyl groups form an angle of 151°).     

Morpholino‐Functionalized and Heteroaryl‐Substituted Titanocene Anti‐Cancer Drugs: Synthesis and Cytotoxicity Studies

From the carbolithiation of 6‐morpholino 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 morpholino‐functionalised titanocenes 5a – c . When these titanocenes were tested against LLC‐PK cells, the IC₅₀ values obtained were of 58, 63 and 115 μM for titanocenes 5a – c respectively. The most cytotoxic titanocene 5a with an IC₅₀ value of 58 μM is found to be approximately 20 times less cytotoxic than cis‐platin, which showed an IC₅₀ value of 3.3 μM, when tested on the LLC‐PK cell line, and 10 times less cytotoxic than its dimethylamino‐functionalised analogue (Titanocene C , IC₅₀ = 5.5 μM).     

6-羟基富烯及环戊二烯并[d][1,2]嗪的合成

由６，６－二烷基富烯与烯丙基格氏试剂加成所得到的取代环戊二烯基负离子与芳酰氯反应，合成了５个未见文献报道的６－羟基富烯化合物（１～５）。用此类化合物与羟胺反应，合成了５个新的环戊二烯并［ｄ］口恶嗪化合物（６～１０），其结构经ＩＲ，１ＨＮＭＲ和元素分析证实。     

Tricarbonyl-6,6′-dimethylfulvene chromium(0) - Structural properties

The crystal structure of tricarbonyl-6,6′-dimethylfulvene chromium(0) was determined using X-ray diffraction at room temperature and at 120 K. The title compound crystallizes in the centrosymmetric, monoclinic space group P2₁/n (no. 14) with one complete molecule in the asymmetric unit. The deviation of the chromium(0) complex from C_s(m) symmetry is negligible in agreement with results derived from density functional calculations using three different methods as well as ab initio calculations (MP2). The 6,6′-dimethylfulvene ligand is bent by 30.9° as a result of the π-η²:π-η²:π-η² coordination to the Cr(0) metal. In addition, the chromium(0) complex was studied by IR and Raman spectroscopy and selected vibrational data are compared to values derived from DFT calculations.     

Traceless Solid‐Phase Synthesis of Cyclopenta[c]quinolines and Cyclopenta[c]chromenes via Hetero [6+3] Cycloadditions of Fulvene. A Facile Approach to the 11‐Heterosteroids Framework

The hetero [6+3] cycloaddition of fulvenes to benzoquinones and iodoanilines provides an efficient route to the synthesis of cyclopenta[c]‐4H‐chromen‐8‐ol, benzo[d]cyclopenta[e]‐3H‐3‐azin‐8‐ol and other 11‐hetero steroids. The structure of the cyclopenta[c]chromene skeleton was confirmed by the X‐ray structure analysis of thep‐bromobenzoate of 39 . A small library consisting of 110 examples was prepared by reacting benzoquinones or iodoanilines with resin 17 .