Podophyllotoxin chemical structures

Chart 1 Chemical structures of colchicine (1), combretastatin A-4 (2), podophyllotoxin (3), vinblastine (4) and vincristine (5)... 

The mechanism of actions involves tubulin binding, reverse transcriptase inhibition, integrase inhibition and topoisomerase inhibition. Podophyllo-toxins bind to tubulin and are able to disrupt the cellular cytoskeleton and interfere with some vital virus processes. There is no relationship between the inhibition of reverse transcriptase (RT) and chemical structure in the case of lignans, because all the chemical antiviral structures are able to bind to the enzyme. As to the rest of the mechanism, there is not much information available. The effects of rabdosiin may be due to its topoisomerase inhibitory effects. Charlton concluded that the antiviral activity of lignans is not strong and that except for podophyllotoxin, which is used topically to treat various warts caused by HPV, none of them are of interest for commercial application. 

Figure 8.5 Chemical structures of podophyllotoxin, etoposide, etopophos, and teniposide.

The GASPE spectrum of podophyllotoxin is shown. The signals at 8 56.0,108.6, and 152.0 each represent two carbons in identical magnetic environments, while the signal at 8 147.6 also represents two carbons that accidentally appear at the same chemical shift. Assign chemical shift values to various protonated and quaternary carbons in the structure. 

The HMQC spectrum of podophyllotoxin shows heteronuclear crosspeaks for all 13 protonated carbons. Each cross-peak represents a one-bond correlation between the C nucleus and the attached proton. It also allows us to identify the pairs of geminally coupled protons, since both protons display cross-peaks with the same carbon. For instance, peaks A and B represent the one-bond correlations between protons at 8 4.10 and 4.50 with the carbon at 8 71.0 and thus represent a methylene group (C-15). Cross-peak D is due to the heteronuclear correlation between the C-4 proton at 8 4.70 and the carbon at 8 72.0, assignable to the oxygen-bearing benzylic C-4. Heteronuclear shift correlations between the aromatic protons and carbons are easily distinguishable as cross-peaks J-L, while I represents C/H interactions between the methylenedioxy protons (8 5.90) and the carbon at 8 101.5. The C-NMR and H-NMR chemical shift assignments based on the HMQC cross-peaks are summarized on the structure. 

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). 

In many cases the isolated natural product may not be an effective drug for any of several possible reasons, but it may nevertheless have a novel pharmacophore. In such cases chemical modification of the natural product structure, either by direct modification of the natural product (semisynthesis) or by total synthesis, can often yield clinically useful drugs. Examples of this from the anticancer area are the drugs etoposide, teniposide, and topote-can, derived from the lead compounds podophyllotoxin and campothecin. 

The first chemical constituent was isolated from podophyllin in 1880 and named podophyllotoxin (97). A structure was proposed in 1932 and after some fine-tuning (98) was shown to be the lignan (60). As might be expected, the crude resin contains a variety of chemical types, including the flavonols quercetin and kaempferol (99). Although these other constituents undoubtedly have biological activity, it is the lignans that have received most attention and to which we shall devote the remainder of this section. 

The Leech Book of Bald (ca. AD 950), a herbalist who lived in the time of Alfred the Great, contains a wealth of plant lore that includes ointments to protect against the elfin race and nocturnal visitors , but also mentions an extract of the wild chervil (probably Myrrhis odorata) as a salve for the treatment of tumours. This plant produces a number of chemicals known as lig-nans, which are related in structure to podophyllotoxin, although much better sources of these cytotoxic lignans are the Himalayan plant Podophyllum... 

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