The variety of biological agents directed toward the tubulin system exceeds those acting on DNA, making it an important target for cancer chemotherapy. However, the complicated chemical structures and restricted access to the natural resources, in combination with the development of drug resistance, limit the first generation of natural products. Considerable efforts in the search and synthesis of new synthetic compounds, such as small molecular tubulin inhibitors, gave access to novel potential/promising drugs. Among these substances, two series of novel, easily accessible indole classes were identified as tubulin-destabilizing agents. Owing to the synthetic nature, potent in vitro and in vivo antitumoral activity, and efficacy against multidrug-resistant (MDR) tumors, D-24851 and D-64131 have significant potential in cancer treatment.
Edelfosine (2-0-methyl-1-0-octadecyl-uuc-glyceryl-3-phosphocholine, 2-N) and miltefosine (hexadecylphosphocholine) are prototypes of new antineoplastically active phospholipids that have been already used clinically. However, oral administration of these drugs to cancer patients was seriously hampered by side effects in the digestive tract (nausea, vomiting, diarrhea, loss of body weight) .['I corresponding animal experiments led us to assume that during the metabolism of these phospholipids, choline esters are formed which imitate the effects of the parasympathetic nervous system on the intestine; such compounds might be responsible at least in part for the symptoms observed in patients and animals. This hypothesis has been supported by the finding that a heterocyclic phospholipid in which choline is replaced by N-(2-hydroxyethyl)-N-methylpiperidine is tolerated much better.[*] In our search for new phospholipids with better tolerability and higher cytostatic activity, special attention was given to the fact that phosphonium and arsonium homologues of choline esters (e.g. of acetylcholine) exert a considerably weaker parasympathomimetic action than the choline esters themselves.[31 Furthermore, it was recently recognized that large amounts of arsonium compounds are ingested with sea food (lobsters, crabs, and clams contain up to 80ppm arsenic; As content of sea water is only 0.003 ppm!) mainly in the form of just slightly toxic compounds such as arsonium betaine and arsonium ~holine.[~. Based on these findings, it seemed possible that replacement of N in choline with As or P would lead to better tolerable but still chemotherapeutically active phospholipids. Accordingly, the biological effects of the new analogues (Scheme l) synthesized to test this working hypothesis were compared to those of the parent compounds 1-N (octadecyiphosphosphocholine) and 2-N. The analogues are derived from the parent compounds by exchange of the central atom of the onium complex while maintaining the hydrophobic octadecyl and octadecylglyceryl residues, respectively. We report here on the syntheses and first results of biological tests with these novel derivatives.The parent compounds 1-N and 2-N were prepared as described previously.['% ' I In the synthesis of [2-(trimethylarsonio)ethyl]-n-octadecylphosphate (1-As) (Scheme l), phosphoryl chloride was treated with n-octadecanol. The resulting n-octadecylphosphoric dichloride was not isolated but treated directly with 2-hydroxyethyltrimethylarsonium bromide (prepared from trimethylarsane and bromoethanol according to Irgolic et al.[*l). The phosphoric diester chloride that formed was hydrolyzed to ,yield 1-As as an inner salt (Scheme 2). The homologous compound 1-P was prepared analogously from n-octadecanol, POCI,, and 2-hydroxyethyltrimethylphosphonium bromide (yield 24 %) .L A 1-AsScheme 2. Synthesis of I-As. a) CHCl,/pyridine/O 'C; b) HO(CH,),As'-(CH,),Br-/pyridine/O "C + 20 "C; c) 10% HCl/purification with ion exchange resin (Amberlite MB3, ethanol)/digestion with acetone; tota...
Dedicated to Ernst B q e r on the occasion of his 70th birthday (24.11.97) The conformational analysis of naturally occurring cytostatic cyclic: heptapeptides axinastatin 2, 3, and 4 was carried out by two-dimensional NMR spectroscopy in combination with distance-geometry (DG) and molecular- In all peptides, a bifurcated H-bond occurs between residue 4 CO and the amide protons of residue 1 and 7. For axinastatin 2 and 3, an Asn 1, turn was found about Asn' and Pro'. We compared these structures with conformations of cyclic heptapeptides obtained by X-ray and NMR studies. A P-bulge motif with two turns and one bifurcated H-bond is found as the dominating backbone conformation of cyclic all-L-heptapeptides. Axinastatin 2, 3, and 4 can be characterized by six fruns and one cis amide bond resulting in a PI/PVI(a)-turn motif, a conformation found for many cyclic heptapeptides. Detailed biological tests of the synthetic compounds in different human cancer cell lines indicates these axinastatins to be inactive or of low activity.
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