Anticancer antibiotics activity

Guanti G, Banfi L, Basso A, Riva R (2005) From natural to rationally designed artificial enedi-ynes towards new anticancer antibiotics activable at will. Chapter 19 in Polyynes Synthesis,... 

Although data presented in the previous section illustrate the diversity of cycloaromatization reactions, most of the following discussion will concentrate on the Bergman cyclization - a reaction that has been studied intensively in recent decades due to its role in the mechanism of biological activity of natural anticancer antibiotics.8,9 We will take advantage of the large body of data produced by this... 

Furanomycin (200), which exhibits antibiotic activity, has been synthesized (80JA887). The novel xanthone psorospermin (488), isolated by Kupchan et al. from Psorospermum febrifugum, was shown to have anticancer activity (80MI31200). 

New oxidatives applications of PSP have been disclosed recently. PSP [as well as polymer-supported sulfide (PSS) [44] mediated Swern oxidation] can efficiently oxidize secondary amines to their corresponding imines [45]. Various pyrrolo[2,l-c][l,4]benzodiazepines 30 (PBDs), a family of compounds showing anticancer and antibiotic activity, have been cleanly prepared following this method (Scheme... 

The study of natural products, or Nature s Combinatorial Library , has had a long history as a source of drugs, and plants have historically been at the forefront of natural product drug discovery. In the anticancer area, for example, vinblastine and vincristine, etoposide, paclitaxel (Taxol), docetaxel, topotecan, and irinotecan, among others, are all plant-derived natural products or modified versions of plant compounds, while antimalarial therapy would be much poorer without quinine and artemisinin and the drugs derived from these plant products. This chapter provides an overview of the major medicinal agents that are themselves natural products isolated from plants or are chemical modifications of such lead compounds. It covers the therapeutic areas of cancer, HIV, malaria, cardiovascular, and central nervous system (CNS) diseases. Natural plant products have also made contributions in areas such as immunomodulatory and antibiotic activities," and the reader is referred to the cited reviews for information on these areas. 

With their unprecedented molecular structures, fascinating mode of action, and phenomenal biological activities, the enediyne anticancer antibiotics have eccited the creative impulses and imagination of many researchers and thus established a vibrant field of investigations. Research in this rapidly evolving field spans areas from computational chemistry, chemical synthesis, molecular recognition, DNA chemistry, and medicine. 

Its unusual challenging structure and significant anticancer and antibiotic activity have attracted the attention of many research groups. More than 200 papers, including reviews (77-81), have appeared so far on its synthesis, cytotoxic mechanism of action, and biosynthesis. This highly active compound against experimental lymphomas was subjected to clinical trials, but its severe toxicity to the hematopoietic system prevented its acceptance into human medicine (82). 

Aryl iodides, bromides, and inflates are used for Sonogashira coupling. But so far few smooth reactions of aryl chlorides with alkynes have been reported. On the other hand, smooth coupling takes place with alkenyl chlorides. The Pd-catalyzed reaction of 1-alkynes with alkenyl chlorides, which are inert in many other Pd-catalyzed reactions, proceeds smoothly without special activation of the chlorides. For example, cw-l,2-dichloroethylene (31) can be coupled with 1-alkynes smoothly, and the coupling has wide synthetic applications, particularly for the synthesis of enediyne structures [30]. The reaction of 31 with two different 1-alkynes is extensively used for construction of highly strained enediyne structures present in naturally occurring anticancer antibiotics such as espermicin and calichemicin [31,32]. The asymmetric (Z)-enediyne 34 can be prepared by a one-pot reaction of 31 with two different 1-alkynes 32 and 33. Similarly the asymmetric ( )-enediyne 37 was obtained in a one-pot reaction of 1-alkynes 33 and 23 with 1,2-dichloroethylene 35. 

Iron-containing pharmaceutical compounds are used and developed as anticancer and antibiotic drugs as well as for treatment of iron deficiency. For instance, Mossbauer spectroscopy was used for studying iron complexes with anticancer antibiotics such as anthracyclines [148], adenosine derivatives [149], and cyclin-dependent kinase inhibitors [ISO]. Sharaby analyzed iron complexes of hexachlorocyclodiphosph(V)azanes of sulfaguanidine (H4L) with antimicrobial activity [151]. Recently, some iron-containing complexes with antituberculosis activity were studied using Mossbauer spectroscopy [152,153]. 

The neoplasm inhibitors, isomitomycin A (52) and albomitomycin A (54) and (56), were isolated, together with mitomycin A from S. caespitosus culture broth. Both antibiotics were obtained by intramolecular rearrangement of mitomycin A [76]. Anticancer antibiotics AX-2 (53) and CX-1 (55) were isolated from the culture broth of S. caespitosus and obtained from mitomycin C [77]. Other biological activities of different mitomycines, their mechanisms of action, and therapeutic utility have been described in various reviews [5, 9, 77-83]. 

Here we present the results of investigations of the physical mechanisms of the interaction with DNA of a new series of biologically-active ligands, analogues of anticancer antibiotic Actinomycin D (AMD), obtained using complex approach involving various experimental biophysical methods and molecular computer modeling. 

The second step in the investigation of the activity of new synthetic anticancer antibiotics (actinocin derivatives) at the molecular level is a detailed study of their complexation with DNA. 

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