Cytotoxic compounds

The search for the bisindole derivatives (22) was originally (81) initiated on the basis of folklore. A brew made from Jamacian periwinkle had estabhshed itself in local medicine as a treatment for diabetes and it was this material that was investigated and found to contain the cytotoxic compounds (22), among others. No materials useful in the treatment of diabetes have been reported from this source. 

One area of research is the replacement of sulfur with selenium to enhance the potency of organic compounds in pharmaceutical apphcations. This has seldom been successflil and often the toxicity is increased. There are some exceptions, eg, selenazofurin, phenylaminoethyl selenide, ebselen, and selenotifen (64). Selenazofurin is a cytotoxic compound having antitumor properties, phenyl aminoethyl selenide is used to reduce hypertension, ebselen inhibits a variety of inflammatory and tissue damaging reactions, and selenotifen is an antiallergic agent. 

Bfx Fx 126 Hypoxic selective cytotoxicity compound 126 DNA-interaction was studied showing poor affinity for this biomolecule [219-222]... 

In cytotoxicity assays the concentration of the cytotoxic compound reaching the cytosol is estimated via its apparent toxicity. Cytotoxicity is expressed as the concentration that inhibits the growth of the MDR-expressing cells by 50% or 20% (known as IC50 or IC2o values, respectively), and indicates whether the secondary, co-administered compound is a substrate or a modulator of P-gp. The activity of the reversal agent is generally expressed as a fold reversion called the MDR ratio [36] ... 

Multidrug resistance (MDR) is the name ascribed to the phenomenon whereby cancer cells and tumors develop resistance to chemotherapeutic agents. Conceptually, this can be viewed as a survival response whereby cancer cells endeavor to ward off cytotoxic compounds. Mechanistically, MDR is typically mediated by overexpression of P-glycoprotein (P-gp aka ABCB1) or other plasma membrane ATPases that export cytotoxic drugs used in chemotherapy, thereby reducing their efficacy. 

Sesbanimide is a novel cytotoxic compound isolated from Sesbania puni-cea seeds [84JCS(P1)1311]. According to high-field H- and C-NMR spectroscopy, in solution a solvent-dependent equilibrium exists between the... 

Histamine may be released from mast cells by mechanisms that do not require prior sensitization of the immune system. Drugs, high-molecular-weight proteins, venoms, and other substances that damage or disrupt cell membranes can induce the release of histamine. Any thermal or mechanical stress of sufficient intensity also will result in histamine release. Cytotoxic compounds, may release histamine as the result of disruption of cell membranes. 

Alkyl 3-dimethyl-2-(177-indol-3-yl)propenoates have found an important role in the synthesis of 3-heteroarylindoles as part of a program aimed at the total synthesis of aplysinopsins and related cytotoxic compounds (Scheme 44)... 

This route is useful in diagnostic studies, by which arterial blood sample may be withdrawn for blood gas studies. Certain cytotoxic compounds are administered by intra-arterial perfusion in localised malignancies. 

FIGURE 10.4 Cytotoxic compounds from Terpios hoshinota. 

Similarly, Aplysina sp.(Fig. 10.7), which show a dramatic change in color from yellow to black when exposed to air, contain cytotoxic compounds including bromotyrosine-derivative alkaloids, purealidins (Ishibashi et ah, 1991 Yagi et ah, 1993), aplysamine 2 (Xynas and Capon, 1989), and purpuramin G (Fattorusso et ah, 1970 Fig. 10.8). 

Cylindramide (90) is a cytotoxic compound isolated from Halichondria cylindrata (7.10 s % wet wt.), but very likely of bacterial origin [148]. The structure was deduced from spectroscopic analysis, the relative stereochemistry (only) of the bicyclo[3.3.0]octene unit by NOESY techniques, and the absolute stereochemistry of the amino acid of the tetramic acid ring (25,35) from the recovery of erythtro-L-(3-hydroxyomithine from oxidative degradation of 90. It showed cytotoxicity to B16 melanoma cells (IC50 0.8 (ig/ml). 

Varacin (114), a cytotoxic compound closely related to lissoclinotoxin A (106), was isolated from a Fijian sample of L vareau and a benzopentathiepin structure was proposed on the basis of spectral data [131]. Two total syntheses of varacin (114) have been carried out [132,133] and later, further syntheses were described [134-135]. N,N-dimethyl-5-(methylthio)varacin (115) and the corresponding trithiane (116) were obtained from L. japonicum from Palau and 3,4-desmethylvaracin (117) was isolated from a Eudistoma sp. from Pohnpei [136], An inseparable mixture of 5-(methylthio)varacin (118) and the corresponding trithiane (119) was obtained from a Pohnpeian Lissoclinum sp. [136]. Three additional antimicrobial polysulfides of the varacin family (120-122) were isolated from Polycitor sp., collected by dredging in the Sea of Japan [137]. 

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