The prevalence of alternative splicing as a target for alterations leading to human genetic disorders makes it highly relevant for therapy. Here we have used in vitro splicing reactions with different splicing reporter constructs to screen 4,000 chemical compounds for their ability to selectively inhibit spliceosome assembly and splicing. We discovered indole derivatives as potent inhibitors of the splicing reaction. Importantly, compounds of this family specifically inhibit exonic splicing enhancer (ESE)-dependent splicing, because they interact directly and selectively with members of the serine-arginine-rich protein family. Treatment of cells expressing reporter constructs with ESE sequences demonstrated that selected indole derivatives mediate inhibition of ESE usage in vivo and prevent early splicing events required for HIV replication. This discovery opens the exciting possibility of a causal pharmacological treatment of aberrant splicing in human genetic disorders and development of new antiviral therapeutic approaches.

Myers's methodology for enantioselective amino acid synthesis was employed to prepare the N-Boc didehydroleucine amide derivative 15 and to effect its conversion into the acylfuran intermediate 17. Coupling of 19 (R = H) with N-(isooctanoyl)serine provided the furan-based analogue 4 of eponemycin (de = 96%), a peptide epoxide with potent cytotoxic and anti-angiogenesis properties. In an identical fashion the corresponding unsaturated analogue 5 of eponemycin was prepared (de = 48%). ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).

A new synthesis of dihydroeponemycin (2), a peptide epoxide with potent cytotoxic and antiangiogenesis activity, has been developed. In the initial steps, Fmoc-Leu-Cl was converted into the key amino ketone intermediate 9 by Stille coupling with tributylvinyltin, conjugate addition of PhSAlMe2 to the derived enone, S-oxidation, and heat-induced syn elimination. Subsequent reaction of 9 with H2O2 and catalytic Triton B produced the corresponding epoxides as a 1:1 diastereomeric mixture in 89% yield. These epoxides were separated and individually converted into 2 and(2S)epidihydroeponemycin (24) in a four-step "one-pot" protocol (77% overall yield in both cases). ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).

Telomeric G-rich single-stranded DNA can adopt a G-tetraplex structure which has been shown to inhibit telomerase activity. We have examined benzoindoloquinolines derivatives for their ability to stabilize an intramolecular G-quadruplex. The increase in Tm value of the G-quadruplex was associated with telomerase inhibition in vitro.

The synthesis of a DNA-cutting agent that conjugates an ellipticine chromophore and a copper complex of bis(salicylidene)ethylenediamine, referred to as a salen, is reported. The presence of the salen Cu complex allows cleavage of DNA via oxygen-based radicals, and the ellipticine moiety serves as a DNA anchor. Spectroscopic measurements indicate that the intercalation geometry of the ellipticine chromophore is preserved with the hybrid. The cleavage is much more efficient with the conjugate than with the Schiff base copper complex alone.

Low light level fluorescence microscopy studies have been carried out on MCF7‐P human mammary tumor cells to localize the intracellular distribtion of two new anticancer drugs, Pazelliptine and Intoplicine, which are currently under clinical evaluation. These two molecules are thought to act at the nuclear level, through DNA topoisomerase interactions. Because fluorescence of these compounds appears strongly quenched by intercalation in double strand DNA, secondary ion mass spectrometry (SIMS) imaging was used to check the presence of the drugs in the nuclear compartment. In spite of chemical structure similitudes, pazelliptine and intoplicine appear to be distributed in quite different ways within the cells. Incubation for 1 and 24 hours also allowed us to bring to light strong differences in the distribution kinetics. Pazelliptine quickly enters into the nucleoli but is no longer present in the nucleus after 24 hours incubation. Intoplicine was not detected by fluorescence in the nucleus, however SIMS microscopy allowed us to show its accumulation within this cellular compartment as a function of time of exposure. This study shows the complementarity of fluorescence and SIMS microscopies. Microsc. Res. Tech. 36:287–295, 1997. © 1997 Wiley‐Liss, Inc.

From 4-N-protected-aminopyridines which were functionalized at their 3-position, 5-azaisatin and equivalent synthons where obtained. Via the use of the Pfitzinger reaction, these compounds provided an easy route to new and various polyheterocyclic compounds.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The photophysical properties of the synthetic drug pazelliptine (PZE) have been investigated in order to characterize the geometric and electronic structure of the molecule bound to DNA. Whatever the pH of the solution, a proton tranfer reaction occurs in the excited state: this leads to the excited 9-N monoprotonated form of PZE. Deexcitation of this excited species is mainly non-radiative. A study of the fluorescence properties of sterically hindered derivatives allows us to propose the existence of a twisted internal charge transfer state to explain this non-radiative deexcitation. The formation of this state occurs on the picosecond timescale (τ∼ 200 ps) when PZE is fully protonated ring nitrogens (i.e. in acidic aqueous solutions).The acido-basic properties of PZE and five related amino and amino-substituted derivatives have been previously studied by spectroscopic measurements. The absorption, fluorescence spectra and the fluorescence quantum yields as a function of pH (range 2–12) and buffer concentration (50 mmol dm–3 to 1 mol dm–3) have been measured. Three pKa values have been determined, at 5.5, 6.5 and 9.2. This is good evidence for PZE having an appropriate pKa when bound to a hydrophobic and/or a hydrophilic structure.

Preparation of pyrano[2,3-h]quinolines containing either a carboxylic acid function or an aminated chain on various positions was achieved. In the course of this investigation, an unusual behaviour of the 4-functionalized chloro- and methoxypyrano[2,3-h]quinoline derivatives towards nucleophiles has been characterized.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

From noracronycine and 1-hydroxy-3-methoxy-10-methylacridone, a [2,3,4-k,l] fused furan ring bearing an ethoxycarbonyl group was built up. Amidification of this ester function with N,N-dimethylaminoalkylamines allowed us to prepare watersoluble furo[2,3,4-k,l]pyrano[3,2-h]acridine and furo[2,3,4-k,I]acridine derivatives. In the course of attempts to saponify the ester function under aqueous sodium hydroxide basic conditions and to reduce it upon aluminium hydride, an abnormal ring opening reaction of the ethoxycarbonylated furan was ascertained.

The effect of 2 ns pulse of 355 nm laser light on aqueous solutions of free pazelliptine (PZE) at different pH and complexed with poly(dA)-poly(dT) was investigated. Spectral analysis revealed the occurence of a photoionization process generating PZE radical cation (PZE(.+)), and the formation of PZE triplet state. The absorption spectrum of the radical PZE(.+) was pH dependent and closely related to the protonated form of PZE in the ground state. Its kinetic evolution appeared very similar for the free drug and for the intercalated complex. By contrast, the triplet state desactivation was different for the free drug and the intercalating complex in deaerated solution. An electron transfer from the poly(dA)-poly(dT) was observed.

Reaction of N-tert-butoxycarbonyl-2-lithioaniline and p-anisidine with 1-hydroxy-3-methoxy-10-methylacridone and noracronycine gave quino[2,3,4-kl]acridines and pyrano[3,2-b]quino[4,3,2-mn]acridines respectively, which are related to biologically active compounds recently isolated from various marine animals.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Alkyl- and aryl-lithiums reacted with noracronycine and 1-hydroxy-3-methoxy-10-methylacridone in a one-step addition–dehydration transformation to provide the corresponding 7- and 9-substituted derivatives having a quinone methide function and, therefore, potential alkylating antitumour properties.