Total synthesis of Camptothecin: - UW-Madison …

Synthetic scheme for total synthesis of Camptothecin ..
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Total synthesis of camptothecin and SN-38.

The antitumor alkaloid 11-hydroxy-(20S)-camptothecin (4) was isolated from the woody tissue of Camptotheca acuminata. Structural proof derived from comparison with racemic 4 prepared by total synthesis. Antitumor activity of racemic 4 in L1210 leukemia in mice was considerably greater than that of natural (20S)-camptothecin (1) and its sodium salt. There was also no toxic effect observed even at relatively high doses.

Total Synthesis of (+)‐Camptothecin. | Request PDF
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19/12/2017 · Total Synthesis of (..

Water-soluble analogues of the antitumor alkaloid camptothecin (1) were prepared in which aminoalkyl groups were introduced into ring A or B. Most of the analogues were prepared by oxidation of camptothecin to 10-hydroxycamptothecin (2) followed by a Mannich reaction to give N-substituted 9-(aminomethyl)-10-hydroxycamptothecins (4-12) or by subsequent modification of Mannich product 4 (13, 15, 17, 19, 21). Others were obtained by modification of the hydroxyl group of 2 (25, 26) or by total synthesis (35, 42, 43). These analogues, as well as some of their synthetic precursors, were evaluated for inhibition of topoisomerase I, cytotoxicity, and antitumor activity. Although there was not a quantitative correlation between these assays, compounds that inhibited topoisomerase I were also cytotoxic and demonstrated antitumor activity in vivo. Further evaluation of the most active water-soluble analogue led to the selection of 9-[(dimethylamino)methyl]-10-hydroxycamptothecin (4, SK&F 104864) for development as an antitumor agent. In addition to its water solubility, ease of synthesis from natural camptothecin, and high potency, 4 demonstrated broad-spectrum activity in preclinical tumor models and is currently undergoing Phase I clinical trials in cancer patients.

| A total synthesis of (+)-camptothecin is described
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A D-E ring analog (XX) of camptothecin (I) was synthesized from 4-methoxy-1-methyl-2 (1H)-pyridone by using Vilsmeier reaction followed by nucleophilic direct introduction of di-tert-butyl malonate onto the pyridone ring, ethylation and hydroxylation.

A total synthesis of (±)-camptothecin - ScienceDirect
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Total synthesis of (±)-17-norcamptothecin, a novel E …

A subset of investigations address DNA binding, alkylation, and cleaving agents that exhibit antitumor activity. These studies include work on CC-1065, duocarmycin A and SA, and yatakemycin where we not only conducted total syntheses of the natural products, defining the absolute stereochemistry and correcting a misassigned structure (yatakemycin), but also characterized their DNA alkylation properties. In these studies, we defined their DNA alkylation selectivity (including that their unnatural enantiomers), rates, reversibility, stereoelectronically-controlled reaction regioselectivity, isolated their adenine N3 adducts, defined the source of their DNA alkylation selectivity (noncovalent AT-rich binding selectivity - shape selective recognition), identified the source of catalysis for the DNA alkylation reaction (DNA binding induced conformation change disrupting the stabilizing vinylogous amide conjugation - shape dependent catalysis), provided high-resolution NMR-derived structures of the natural products bound to DNA, and established that they are subject to an exquisite "target-based activation". More than 135 publications and more than 2000 analogs of the natural products (e.g., CBI) have been disclosed containing deep-seated structural changes used to define relationships between structure and reactivity or structure and activity, and their contributions to the expression of the DNA alkylation properties and biological activity of the natural products (e.g. "hydrophobic binding-driven-bonding" and the predictive parabolic relationship between reactivity and the biological potency). Analogous studies on bleomycin (30 publications, ca. 100 analogs probing each substiutent and each subunit in structure) confirmed the origin of DNA cleavage selectivity derived from G triplex-like H-bonding in the minor groove, defined fundamental conformational properties contributing to the efficiency of DNA cleavage, and provided a high resolution NMR-derived structure of DNA bound deglycobleomycin A2. We prepared a >9000-membered screening library of distamycin analogs, discovered and defined the DNA cross-linking properties of ischrysohermidin and established the origin of its selectivity, and have studied the naturally occuring bis-intercalators (sandramycin, luzopeptins, quinoxapeptins, thiocoraline, BE-22179), defining their DNA binding selectivity, its origins, kinetics of binding, and established a high resolution NMR-derived structure of sandramycin bound to DNA. In the course of these studies, we introduced the powerful fluorescent intercalator displacement (FID) assay for establishing DNA binding selectvity or affinity that complements footprinting and a convenient M13-derived alternative to 32P-end-labeling of restriction fragments for DNA cleavage studies.

process for asymmetric total synthesis of camptothecin

Both enantiomers of 20-fluorocamptothecin and the racemate have been prepared by total synthesis. The (R)-enantiomer is essentially inactive in a topoisomerase-I/DNA assay, while the (S)-enantiomer is much less active than (20S)-camptothecin. The lactone ring of 20-fluorocamptothecin hydrolyzes more rapidly than that of camptothecin in PBS. The results provide insight into the role of the 20-hydroxy group in the binding of camptothecin to topoisomerase-I and DNA.