Antitumour compounds

Review Problem 3 Tliis odd-looking molecule (TM 34) was used by Corey as an intermediate in the synthesis of maytansine, an antitumour compound. 

P. Potier, Rhone-Poulenc Lecture. Search and discovery of new antitumour compounds, Chem. Soc. Rev., 21 (1992) 113-119. 

Sedletska Y, Giraud-Panis MJ, Malinge JM (2005) Cisplatin is a DNA-damaging antitumour compound triggering multifactorial biochemical responses in cancer cells importance of apoptotic pathways. Curr Med Chem Anticancer Agents 5(3) 251-265... 

Ellipticine inhibits DNA, RNA and protein synthesis. The inhibition is not reversible by removal of the alkaloid. It has no appreciable effects on thymidine and uridine kinases or on RNA polymerase, but it markedly inhibits DNA polymerase activity [240, 241]. The actual mechanism of action of ellipticine and related compounds has not yet been elucidated. Ellipticine and derivatives have been found to interact with bacterial membranes [242]. Many investigators have categorized these compounds as DNA-interacting or intercalating agents [230, 235, 237,243-246]. It has recently been postulated that mammalian DNA topoisomerase II may be a common target of these antitumour compounds [247],... 

Kondoh, M., Usui, T., Nishikiori, T., Mayumi, T., and Osada, H. (1999). Apoptosis induction via microtubule disassembly by an antitumour compound, pironetin. Biochem.J. 340, 411-416. 

Hydroxynoracronycine (40) is a constituent of Atalantia ceylonica and a metabolite of the antitumour compound acronycine its synthesis has been reported (Scheme 6).31 The reaction of l,3-dihydroxy-5-methoxy-9-acridone (36) with 3-chloro-3-methylbut-l-yne and cyclization in situ of the products furnished the chromenes (38) and (39) the formation of the intermediate (37) involves C-alkylation with the chlorobutyne, a reaction encountered previously during the synthesis of flindersine.32 Chromene (39) was converted into 11-hydroxy-noracronycine by successive methylation and demethylation. 

Finally, the compounds in the margin form a medicinally important group of molecules, which includes antitumour compounds for humans and anthelmintics (compounds that get rid of parasitic worms) for animals. They are derived from a 6/5 fused aromatic ring system that resembles the ten-electron system of the indolizine ring system but has three nitrogen atoms. 

For some indoles it is necessary to control regioselectivity with nnsymmetrical carbonyl compounds. Ondansetron, the anti-nausea compound that is used to help cancer patients take larger doses of antitumour compounds than was previously possible, is an example. It contains an indole and an imidazole ring. 

An important shikimate metabolite is podophyllotoxin, an antitumour compound—some podophyllotoxin derivatives are used to combat lung cancer. The compound can be split up notion-ally into two shikimate-derived fragments (shown in red and green). Both are quite different and therejjs obviously a lot of chemistry to do after-the shikimic acid pathway is finished. 

Camptothecins. The alkaloid camptothecin from Camptotheca acuminata (Nyssaceae) and Mappiafoetida (Icacinaceae) has a pyranoindolizoquinoline structure (Phe pyridine C4N C5N C5L) involving the fusion of quinoline (Phe pyridine), indolizidine (C4N C5N ) and C5 lactone (C5L) rings. Camptothecin is a topoisomerase I inhibitor and is a potent cytotoxic and antitumour compound that is used clinically as an anticancer... 

Jatrophanes (C5 C12) are cytotoxic, antitumour compounds from Jatropha species (Euphorbiaceae). Jatrophone binds to DNA and also has activity as a glutamate receptor antagonist. 

The carbamate 120 is lithiated with. sec-butyl lithium to form the intermediate 121 that reacts further to form the amide 122. From the ort/zo-lithiation point of view we now have a different ort/to-director in the molecule and, if we protect the phenol group, we can continue lithiation around the ring. This chemistry was used in the synthesis of the diene 124 needed for the antitumour compound pancratistatin23 123. 

This may look like a rather specialised method but the biomimetic inspiration applies to much simpler compounds. Taxodione 261 is an antitumour compound from the swamp cypress Taxo-dium distichum. It has an extended quinone-like enone system and two trans fused six-membered rings. Livinghouse42 realised that the extended quinone might be derived by oxidation of a simpler aromatic compound 262 where X is an oxidisable group. He then saw a possible polyolefin cyclisation in which a tertiary cation derived from a simple alkene 263 starts the reaction and the aromatic ring terminates the sequence. 

We give two examples an anti-ulcer drug with three heterocyclic rings and an anti-viral and antitumour compound, pentostatin. 

Pratt and Raphael needed the cyclohexenone (1) for a synthesis of the antitumour compound vernolepin. Disconnection of the a ,0 bond reveals the basic skeleton (2) no FGI is needed as all the FGs are carbonyl groups. 

The D-glucose derivative (49) serves as a convenient source for preparing both enantiomers of the precursor (50) for the antitumour compound sesbanimide. Scheme 11 outlines the synthesis of the D-enantiomer the L-form was obtained by demasking the aldehyde at... 

A short synthetic sequence to a benzazocenone 46, a potential building block for mito-mycenoids and related antitumour compounds, makes use of an intramolecular addition... 

The addition of singlet oxygen to the furanolactone (166) gave a quantitative yield of the pseudo-acids (167) and (168) which were converted into the antitumour compound camptothecin (169) in three steps (Scheme 48). Other important uses of the Diels-Alder addition of singlet oxygen to dienes are in the synthesis of cw-l,4-dihydroxycyclopentene from cyclopentadiene/ and in the preparation of analogues of prostaglandin endo-peroxide. ... 

Benzenetriols on cyclocondensation with hydroxybenzoic acids gave 1,3-dihydroxyxanthones which were converted into various 0-derivatives containing carboxyl or amino groups.Several xanthones [e.g., (165)] have been synthesized by ring closure of the ketones (164) with ethanolic potash.Benzoxanthones are represented in nature by several compounds such as the quinone bikaverin. Several members of this class [e.g., (166)] were prepared by base-induced condensation of 2-hydroxyacetophenones with dimethyl homophthalates, and reduced benzoxanthanone (167) which is potentially of interest as an antitumour compound, was obtained by condensation of 2-methylchromone-3-carboxylic acid with methyl 4-oxocyclohexanecarboxylate. 

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