Saccharothrix aerocolonigenes ATCC 39243 produces an indolocarbazole antitumor agent rebeccamycin under submerged fermentation conditions. Adding DL-6-fluorotryptophan to culture of S. ...aerocolonigenes ATCC 39243 induces the formation of two novel indolocarbazoles, fluoroindolocarbazoles A and B. Feeding DL-5-fluorotryptophan to culture of S. aerocolonigenes ATCC 39243 induces the production of a novel indolocarbazole, fluoroindolocarbazole C. These fluoroindolocarbazoles have been isolated from culture broth and purified to homogeneity by vacuum liquid chromatography and column chromatography. All three fluoroindolocarbazoles are more potent than rebeccamycin against P388 leukemia by ip route in murine model.
The reductive conversion of ribonucleotides to deoxyribonucleotides by ribonucleotide reductase (RR) is a crucial and rate-controlling step in the pathway leading to the biosynthesis of DNA, since ...deoxyribonucleotides are present in extremely low levels in mammalian cells. Mammalian ribonucleotide reductase (RR) is composed of two dissimilar proteins, often referred to as R1, which contains polythiols and R2, which contains non-heme iron and a free tyrosyl radical. Both the R1 and R2 subunits contribute to the active site of the enzyme. Currently, there are two broad classes of RR inhibitors. The first class includes nucleoside analogs which bind to the R1 subunit of the enzyme, several of which are in development. Among those, Gemcitabine and MDL 101,731 have demonstrated impressive efficacy against various solid tumors. Gemcitabine has now been approved for the treatment of pancreatic cancer and non-small cell lung cancer. The most promising second class of inhibitors of RR includes HCTs α-(N)-heterocyclic carboxaldehyde thiosemicarbazones, e.g., 3-AP and 3-AMP, which exert enzyme inhibitory effect through high affinity binding with non-heme iron. Based on the clinical success achieved by Gemcitabine, it seems reasonable that a strong inhibitor of RR, which is essential for cellular replication, would be a useful addition to the existing therapeutic agents against cancer. In this chapter, we wish to report several highly efficient syntheses for both 3-AP and 3-AMP based upon palladium mediated Stille/Suzuki/Heck coupling reactions. Based upon the in vivo efficacy profile observed with these two agents, 3-AP was chosen over 3-AMP as the candidate for further optimization with the intention to improve its biological and pharmaceutical properties. In this vein, we have completed the synthesis of two water soluble phosphate containing prodrugs and one disulfide-linked prodrug of 3-AP. As expected, bioconversion study using either alkaline phosphatase or glutathione showed that these prodrugs were indeed converted to the parent 3-AP. When evaluated against the murine M-109 lung carcinoma as well as the B16-F10 murine melanoma xenograft models, the newly prepared phosphate prodrugs displayed improved efficacy and safety profiles than that found with the parent. More significantly, the ortho-phosphate prodrug 21 demonstrated impressive antitumor effect using once-a-day dosing regimen. In summary, the results disclosed herein demonstrated that some of 3-AP prodrugs prepared indeed demonstrated improved pharmaceutical, biological and toxicity profiles over the parent 3-AP. Efforts directed towards further optimization of 3-AP prodrugs as novel anticancer agents is clearly warranted.
The internalizing anti-Le(y) monoclonal antibody (MAb) BR64 was conjugated to the anticancer drug doxorubicin (DOX) using an acid-labile hydrazone bond to the DOX and either a disulfide or thioether ...bond to the MAb. The resulting disulfide (BR64-SS-DOX) and thioether (BR64-S-DOX) conjugates were evaluated for stability, potency, and antigen-specific activity in both in vitro and in vivo model systems. The BR64-SS-DOX conjugates demonstrated antigen-specific activity both in vitro and when evaluated against antigen-expressing, DOX-sensitive human carcinoma xenografts. However, the stability and potency of disulfide conjugates were poor, and in vivo activity superior to unconjugated DOX was seen only at doses approaching the maximum tolerated dose. Furthermore, BR64-SS-DOX conjugates were not active against antigen-expressing, DOX-insensitive colon tumor xenografts. In contrast, the BR64-S-DOX conjugates demonstrated good stability both in vitro and in vivo. The increased stability of the BR64-S-DOX conjugates resulted in the delivery of more biologically active DOX to tumors with a concomitant increase in potency and efficacy over that which could be achieved with either unconjugated DOX or BR64-SS-DOX conjugates. Delivery of DOX by BR64-SS-DOX conjugates resulted in complete regressions and cures of both DOX-sensitive lung xenografts and DOX-intensitive colon tumor xenografts. These results demonstrate the importance of linker stability when delivering drugs such as DOX to carcinomas via internalizing antibodies and are likely to have direct relevance to the clinical utility of MAb-directed delivery.
Several C-13 amidopaclitaxel analogs have been synthesized during the course of our structure−activity relationship study at the C-13 position. These include 4-deacetyl-13-amidopaclitaxel (4), ...13-amidopaclitaxel 4-(methyl carbonate) derivatives (5a,b), and 13-amidopaclitaxel (6). None of these novel C-13 amidopaclitaxel analogs retain any activity in the tubulin polymerization assay or the in vitro cytotoxicity assay.
The synthesis, pharmacokinetic properties, and antitumor evaluation of novel paclitaxel phosphonooxymethyl ether derivatives
8–11 and salts thereof is described. These compounds exhibit improved ...water solubility as compared to paclitaxel (
1) and upon incubation with plasma and alkaline phosphatase they readily release parent drug. The
in vivo
antitumor evaluation of compounds
8–11 established them as suitable pro-drugs of paclitaxel.
Pharmacokinetic and antitumor data (in vivo, in mice) established synthesized compounds as suitable pro-drug candidates of paclitaxel.
The chemistry of DNA cleavage by the esperamicins A sub(1), C, D, and E (esp A, C-E) has been examined. High-resolution gel electrophoresis reveals that esp A, a known single-strand cleaver, affords ...fragmentation products consistent with exclusive 5'-hydrogen abstraction. In contrast, esp C-E, analogs that produce significant double-strand cleavage, generate fragmentation products consistent with both 5'- and 4'-hydrogen abstraction. On the basis of these observations and other findings reported for a related enediyne antibiotic, calicheamicin gamma sub(1) super(I), we conclude that 4'-hydrogen abstraction and bistranded DNA cleavage are directly related to the reactivity of the C-7 radical as modulated by the fucosyl-anthranilate group.
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