Antineoplastic agents 285. Isolation and structures of cephalostatins 14 and 15

Abstract

,2260 (1994).The tube-inhabiting marine worm, Cephalodiscus gilchristi has been found to produce a series of cytotoxic and antineoplastic disteroidal alkaloids. A substantial study concerned with discovery of new cell growth inhibitory constituents of this marine animal has led to isolation of cephalostatins 14 (50) and 15 (5b). The structures were determined by interpretation of spectral data, principally high-field (400 and 500 MHz) NMR and HRFABMS combined with NMR spectral relationships to cephalostatin 1 (4) where the structure was previously assigned by X-ray crystal structure analysis. The stereochemical assignments were established employing the ROESY NMR technique. Both new cephalostatins significantly inhibited growth of the P388 lymphocytic leukemia and a selection of human cancer cell lines. The two new cephalostatins further enhance knowledge of structure-activity parameters for these potentially important steroidal alkaloids. On a trouvC que le ver marin habitant un tube, Cephalodiscus gilchristi, produit une sCrie d'alcaloi'des distCroi'daux cytotoxiques et antinCoplastiques. Une Ctude importante relative B la dCcouverte de nouveaux constituants de cet animal marin inhibants la croissance de nouvelles cellules a conduit B I'isolement des cephalostatines 14 (50) et 15 (5b). On a dCtermini le structures par I'interprCtation des donnCes spectrales obtenues principalement par RMN A champ ClevC (400 et 500 MHz) et par HRFABMS combink avec des relations spectrales avec la ctphalostatine 1 (4) dont la structure a Cte attribuCe anterieurernent par diffraction des rayons X. Les attributions stCrkochimiques ont Ct C faites par la technique REOSY de la RMN. Les deux nouvelles cCphalostatines inhibent fortement la croissance de la leuctmie lymphocytaire P388 ainsi qu'une selection de cellules humaines can&reuses. Les deux nouvelles ~Cphalostatines augmentent nos connaissances sur les paramktres structure-activitC de ces alcaloi'des stCroi'daux potentiellement importants.[Traduit par la ridaction]

Synthesis of chiral building blocks for cephalostatin analogues

“…This observation appears to be in line with the coordination approach suggested by Kajiro [19]. Additionally the use of Sc(OTf) 3 in the present case resulted in hydrolysis of acetate group selectively and there was no indication of hydrolysis of the pivalate group. Both the hydrolysis products (20) and (21) were found to have the pivalate group retained in there structure.…”

“…However all such efforts remained unsuccessful. However, when aectoxyketone (19) was treated with scandium triflate (Sc(OTf) 3 ) in a mixture of methanol and water (1:4) at 60-65 °C for 24 hours, the desired 6-hydroxy-5-ketone (20) was obtained in 30% yield, along with 3,6-dihydroxy-5-ketone (21) in 13% yield. It may be emphasized that (20) was obtained in relatively better yield because formation of (20) from (19) by use of Sc(OTf) 3 had involved the carbonyl group adjacent to the acetate group during hydrolysis.…”

“…Cephalostatins are natural products isolated from the marine worm Cephalodiscus gilchristi [1] . Cephalostatins are among the most potent cytostatics ever screened by NCI [2,3] and therefore have potential applications as anti-tumour agents e.g., cephalostatin 1 has exhibited remarkable cytotoxic activity against P388 murine leukemia cells with IC 50 values of 10 -4 -10 -6 ng/ml [4]. The structure of cephalostatins consist of a central pyrazine and two C27 steroidal units on each side (1).…”

Synthesis of steroidal dimers: Selective amine catalysed steroidal dimerization

“…10,11 Most of the steroidal dimmers are also well-known for their pharmacological activity. [12][13][14][15][16][17] It might be expected that polymers of steroidal ketones (or ketone derivatives) would readily be formed in reaction media of amine catalysed dimerization. 18 Here we are presenting new dimeric steroids namely cholest-5-en-3-spiro-[6 α,5 -oxa]-5 α-cholest-3 -one (2), cholest-5- * For correspondence en-7-spiro-[4 α,5 -oxa]-5 α-cholest-7 -one (4a) and 3β-substituted-cholest-5-en-7-spiro-[4 α,5 -oxa]-3 β-substituted-5 α-cholestan-7 -ones (4b, c) which were prepared from cholest-5-en-3-one (1), cholest-5-en-7-one (3a) and 3β-substituted-cholest-5-en-7-ones (3b, c), respectively by amine catalysed dimerization 18 using DMAP and xylene.…”

Schweinfurthins as novel anticancer agents

“…The initial description of cephalostatin 1 was followed by the isolation and identification of cephalostatins 2, 3, and 4, which display similar potency ( Figure 3) [78,79]. At present, nineteen members of the cephalostatin family have been identified [78][79][80][81][82][83][84][85][86]. While all of these compounds are potent inhibitors of proliferation in P388 cells, cephalostatins 1, 2, 3, 4, 7, 8, and 9 are the most potent ( Figure 3) [87].…”