Antimitotic activity

The active principle of the autumn crocus (Colchicum autumnale), colchicine (48), is one of the very few drugs that have remained in reputable medical use since ancient times. This drug was the only useful treatment available for the excruciating pain associated with crystallization of uric acid in the joints characteristic of gout until the advent of allopurinol. Although the precise mechanism by which colchicine gives this dramatic relief remains undefined, the antimitotic activity of this agent is... 

Finally, the report by Angenot et al. of an exceptional increase of antimitotic activity in strychnopentamine (104) caused by the presence of a supplementary pyrrolidine ring, is worth noting (199). Chemists might use this fact as an reason to promote interesting new syntheses of pyrrolidine alkaloids or creation of unnatural molecules containing pyrrolidine. 

The cause of the cell cycle specificity of the bisindole alkaloids may be associated with the ability of these compounds to interact with the protein tubulin and thereby inhibit the polymerization (and depolymerization) of microtubules (16,17). In this respect the cellular pharmacology of vinca alkaloids is similar to that of other cytotoxic natural products such as colchicine or podophyllotoxin. On closer inspection, however, Wilson determined that the specific binding site on tubulin occupied by vinblastine or vincristine is chemically distinct from the site occupied by the other natural products (18). Subsequent experiments have determined that the maytansinoids, a class of ansa-macrocycles structurally distinct from the bisindoles, may bind to tubulin at an adjacent (or overlapping) site (19). A partial correlation of the antimitotic activity of these compounds with their tubulin binding properties has been made, but discrepancies in cellular uptake probably preclude any quantitative relationship of these effects (20). 

Indications for glucocorticosteroids include adrenal insufficiency and inflammatory, non-infectious processes of all sorts such as various types of arthritis, auto-immune diseases, asthma, inflammatory bowel diseases, especially Crohn s disease but also ulcerative colitis and further many skin diseases and some diseases of the eye. Their antimitotic activity is used in various anti-cancer chemotherapeutic regimens. They still have an important place... 

The antimitotic activity of several Amaryllidaceae metabolites has been emphasized (79a, 79b), although, in the case of narciclasine (376), the considerable degree of toxicity seemed to prevent its clinical use. 

Sirolimus (Rapamycin, Rapamune ), a natural macrocyclic lactone, is a potent immunosuppressive agent. It was developed by Wyeth-Ayerst Laboratories (Philadelphia, Pennsylvania, U.S.A.) and approved by the Food and Drug Administration for the prophylaxis of renal transplant rejection in 1999 (28,29). Sirolimus has its roots in Easter Island, where an actinomycete streptomyces hygroscopicus was found that produced a novel macrolide antibiotic with potent antibiotic, potent antifungal, immunosuppressive, and antimitotic activities. 

ABSTRACT Numerous molecules containing a biaryl unit have been found in Nature. Many of them exhibit a variety of biological actions. In this review, we will focus only on natural bridged biaryls that possess axial chirality and exhibit antimitotic activities. Thus, we will first present the occurrence and structure of three families of natural compounds that display these particular structural and biological features the allocolchicinoids, steganes and rhazinilam-type compounds. We will then describe the semi-synthetic and synthetic approaches to biaryls belonging to these three series. Their interaction with tubulin, a heterodimeric protein that is critical for the formation of microtubules and consequently of the mitotic spindle, will be discussed. 

Remillard, S., Rebhun, L.I. Antimitotic activity of the potent tumor inhibitor Maytansine. Science 189, 1002 (1975)... 

Gueritte-Voegelein, R Guenard, D. Lavelle, R Le Goff, M.-T. Mangatal, L. Potier, P. Relationships between the structure of taxol analogs and their antimitotic activity. J. Med. Chem., 1991, 34 992-998. 

The trisaccharide chain in Cinerubin A, an anthracycline antibiotic with antimitotic activity, has been replaced by a poly(ethylene glycol) The resulting poly(ethylene oxide)-bound e-pyrromycinone is readily soluble in water and exhibits full biological activity. In this case, the hydrophilic poly(ethylene oxide) chain appears to be perfectly suitable to simulate the physicochemical properties of the oligosaccharide chain. 

Antimitotic activity suppresses proliferation of keratinocytes, fibroblasts and lymphocytes (useful in psoriasis, but also causes skin thinning)... 

The completion of the total synthesis of 7,ll-e/ /-thyrsiferol (140), a novel analogue of the thyrsiferol family of compounds, prompted us to investigate its potential anticancer properties. To examine the pharmacological profile of 140, we selected sea urchin embryos as a biological system for the in vitro evaluation of antimitotic activity [76]. 

A preliminary screen of the antimitotic activity of l, -epi-thyrsiferol (140) using the sea urchin assay established that this compound inhibits the first cleavage of S. purpuratus embryos in a concentration dependent manner with 50% inhibition occurring at approximately 7 pg/mL [11 pM, Fig. (9)]. At a concentration of 30 pg/mL (48 pM), this compound produced 100% inhibition of the first mitosis without lysis or morphological abnormalities at any of the concentrations used [77]. 

The pharmacological results just presented have established the antimitotic activity of compound 140 to be 7 pg/mL [11 pM, Fig. (9)] in the sea urchin assay. A comparison between the antimitotic activitiy of synthetic analogue 140 with the naturally occurring products 1 and 3 determined thyrsiferol (1) to be the most potent substrate among the three compounds tested (Table 4). 

The enantioselective total synthesis of (-)-hemiasterlin, a marine tripeptide with cytotoxic and antimitotic activity, was achieved by E. Vedejs and co-workers. The asymmetric Strecker reaction was used to construct the key tetramethyltryptophan subunit. The aldehyde substrate was first converted to the corresponding chiral imine with (R)-2-phenylglycinol under scandium triflate catalysis. The addition of tributyltin cyanide resulted in the formation of a-amino nitriles as an 8 1 mixture of diastereomers. Subsequently the cyano group was converted to a primary amide, and the chiral auxiliary was removed under catalytic hydrogenation conditions. 

The first total synthesis of ( )-lycoridine margetine (33), a member of the non-basic alkaloids which possess antimitotic activity has been achieved (Scheme 3). The homoallylic alcohol (26) served as a latent diene in a Diels-Alder reaction with ethyl acrylate to give a diastereomeric mixture of adducts which upon base equilibration and hydrolysis provided the tmns-acid (27). Modified Curtius reaction on (27) afforded the corresponding isocyanate which was cyclized to the lactam (28) in 89% yield by a new method using boron trifluoride etherate. Compound (28) was converted into an N-acetyl derivative which upon basic hydrolysis gave the acid (29). Treatment of (29) with NBS followed by reflux in pyridine solution gave the lactone... 

Among the 6-membered heterocombretastatins, where the B ring was replaced by a variety of 6-membered heterocycles (pyridines, pyrimidines, pyridazines, pyrazines, pyridinium salts) the pyridone derivative 14 showed strong antimitotic activity IC50 2 jiiM, the same value of Combretastatin A-4) and cytotoxicity IC50 19.2 nM, versus 8.7 nM of Combretastatin A-4), along with excellent water-solubility. 

The pyrazole- and thiazole analogues of the 3 -deoxy-3 -amino-4 -methoxy Combretastatin A-4 showed potent antimitotic (IC50 3.0 pM and IC50 10 pM) activity. The former showed also a potent cytotoxic activity (IC50 8.4 nM ). Moderate antimitotic activity (IC50 3.0 pM) and weak cytotoxic activity was observed for a triazole derivative, whereas tetrazole ring confers potent antimitotic (ICso 2.0 pM) as well as cytotoxic activity. Compounds with potent cjdotoxicity were further evaluated in vivo in the Colon murine tumor model. The best antitumor activity in vivo, expressed as tumour growth suppression, was observed for the thiazole and tetrazole derivatives with values comparable to the ones observed for 3 -deoxy-3 -amino Combretastatin A-4 hydrochloride. 

The phenanthrenoids from Bletilla striata showed similar antimitotic activity to bibenzyls in the same plant, but less potent (ICso 30 / M) than the bibenzyls [468]. 

Whether the resulting aniline derivative can also be a source of antimitotic activity does not appear to be established but the toxicity of aniline derivatives Is well known (18-20). The antimitotic activity Is generally believed to occur via the... 

In medicine too these compounds are of interest and a variety of pharmaceutical products are based on heterocyclic thioxo compounds containing nitrogen atoms in the ring. Among these are diuretics, aiiti-malarials, antitumors, cytostatica, coronary vasodilators, myocardial stimulants, products with antimitotic activity or with dermatological and disinfectant properties. 

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