Targeted inhibition of hedgehog signaling by cyclopamine prodrugs for advanced prostate cancer.

A promising agent for use in prostate cancer therapy is the Hedgehog (Hh) signaling pathway inhibitor, cyclopamine. This compound, however, has the potential for causing serious side effects in non-tumor tissues. To minimize these bystander toxicities, we have designed and synthesized two novel peptide-cyclopamine conjugates as prostate-specific antigen (PSA)-activated prodrugs for use against prostate cancer. These prodrugs were composed of cyclopamine coupled to one of two peptides (either HSSKLQ or SSKYQ) that can be selectively cleaved by PSA, converting the mature prodrug into an active Hedgehog inhibitor within the malignant cells. Of the two prodrugs, Mu-SSKYQ-Cyclopamine was rapidly hydrolyzed, with a half-life of 3.2h, upon incubation with the PSA enzyme. Thus, modulating cyclopamine at the secondary amine with PSA-cleavable peptides is a promising strategy for developing prodrugs to target prostate cancer.

Modulating paclitaxel bioavailability for targeting prostate cancer.

Four novel water-soluble peptide-paclitaxel conjugates were designed and synthesized as prostate-specific antigen (PSA)-activated prodrugs for prostate cancer therapy. These prodrugs were composed of a peptide, HSSKLQ or SSKYQ, each of which is selectively cleavable by PSA; a self-immolative linker, either para-aminobenzyl alcohol (PABS) or ethylene diamine (EDA); and the parent drug, paclitaxel. Introduction of a PABA or EDA linker between the peptide and paclitaxel in prodrugs 2-5 resulted in products with an increased rate of hydrolysis by PSA. The stability of prodrugs 2 and 3, with the PABA linker, was poor in the serum-containing medium because of the weak carbonate bond between the PABA and paclitaxel; however, this disadvantage was overcome by introducing a carbamate bond using an EDA linker in prodrugs 4 and 5. Thus, the incorporation of an EDA linker increased both the stability and PSA-mediated activation of these prodrugs. The cytotoxicity of each prodrug, as compared to paclitaxel, was determined against a variety of cell lines, including the PSA-secreting CWR22Rv1 prostate cancer cell line. The EDA-derived prodrug of paclitaxel 5 was stable and capable of being efficiently converted to an active drug that killed cells specifically in the presence of PSA, suggesting that this prodrug and similarly designed PSA-cleavable prodrugs may have potential as prostate cancer-specific therapeutic agents.

Sesquiterpenes: natural products that decrease cancer growth.

Despite recent advances in our understanding of the biological processes leading to the development of cancer, there is still a need for new and effective agents to help bring this disease under control. One of the oldest and most effective strategies for developing new chemotherapeutics is the isolation and evaluation of chemicals of natural origin. The importance of natural products for drug discovery has been impressive: One has to only look at the number of clinically active drugs that are used in cancer therapy to see how many are either natural products or are based on natural products. It is also apparent that materials from natural sources are excellent probes (indicators) for cellular targets that, when modulated, may have a deleterious effect upon the survival or proliferation of tumor cells. And the search goes on. Sesquiterpenes are a class of naturally occurring molecules that have demonstrated therapeutic potential in decreasing the progression of cancer. These molecules are 15-carbon isoprenoid compounds that are typically found in plants and marine life. Although this class of compounds has frequently provided encouraging leads for chemotherapeutics, they have not been evaluated as potential anticancer agents. In this review, we provide a current overview of sesquiterpenoids that have potential as anticancer agents.

Bis(carbamoyloxymethyl) esters of 2',3'-dideoxyuridine 5'-monophosphate (ddUMP) as potential ddUMP prodrugs.

PURPOSE: We previously reported the synthesis of bis(pivaloyloxymethyl) 2',3'-dideoxyuridine 5'-monophosphate (POM2-ddUMP) (1a) as a membrane-transport prodrug formulation of the free parent nucleotide, ddUMP. Although successful at delivering ddUMP into cells in culture, POM2-ddUMP was rapidly degraded by plasma carboxylate esterases after intravenous administration to experimental animals, and therefore has limited therapeutic potential as a systemically administered prodrug. We now report the synthesis of bis(N,N'-dimethylcarbamoyloxymethyl)- and bis(N-piperidinocarbamoyloxymethyl) 2',3'-dideoxyuridine 5'-monophosphate [DM2-ddUMP (1b) and DP2-ddUMP (1c), respectively], analogues of POM2-ddUMP that were designed to be more resistant to degradation by plasma esterases. METHODS: After entering cell by passive diffusion, it was anticipated that loss of one of the carbamoyloxymethyl groups of 1b and 1c would occur by spontaneous chemical hydrolysis to give the intermediate phosphodiesters, 2b and 2c. Cleavage of the remaining carbamoyloxymethyl groups by cellular phosphodiesterase I would generate ddUMP. 1b and 1c were prepared by condensation of 2',3'-dideoxyuridine (ddU) with the appropriate bis(N-alkylcarbamoyloxymethyl) phosphate in DMA in the presence of triphenylphosphine and diethyl azodicarboxylate (the Mitsunobo reagent). RESULTS: The half-lives of 1b and 1c when incubated at a concentration of 10(-4) M in human plasma at 37 degrees C were 3.5 h and 3.7 h, respectively, similar to the half-lives observed under the same temperature conditions in 0.05 M aqueous phosphate buffer, pH 7.4. By contrast, the half-life of the POM2 prodrug, 1a, in plasma was only 5 min. The initial products of degradation of 1b and 1c were the phosphodiesters 2b and 2c. The latter compounds gave rise to ddUMP when incubated with snake venom phosphodiesterase I. CONCLUSION: These findings support the premise inherent in the design of 1b and 1c, namely that the carbamate prodrugs are far more resistant to hydrolysis by plasma carboxylate esterases than their POM counterparts and can revert to the free parent 5'-mononucletides by successive chemical and enzymatic hydrolysis. Further studies of 1b and 1c as membrane-permeable prodrugs of ddUMP are in progress.

Design, synthesis and biological evaluation of novel riccardiphenol analogs.

A novel, facile, high yield, and less cumbersome synthesis of riccardiphenol analogs is described. The synthesized compounds were characterized and assessed for its in vitro activity in a panel of human cancer cell lines of differing origin: HuCCT-1, BxPC3, Panc-1, Mia-Paca, A431, Hep2, and HN006. HuCCT-1 was derived from an intrahepatic cholangiocarcinoma; BxPC3, Mia-Paca, and Panc-1 were derived from pancreatic cancers; A431 was derived from a vulvar epithelial carcinoma; and Hep2 and HN006 were derived from squamous cell carcinomas of the head and neck. The cytotoxicity of a newly developed riccardiphenol analog against human cancer cell lines was assessed. The cancer cells exhibited varying sensitivities to the compound, with IC50 values from 30 to 50 microM. This susceptibility was particularly interesting in the case of lines such as Hep2 and BxPC3 that are resistant to classic cytotoxic drugs as well as some targeted agents. These results demonstrate that the novel riccardiphenol analog has effective action against human-derived cancer cell in vitro.

Design, synthesis, and evaluation of novel boronic-chalcone derivatives as antitumor agents.

A series of boronic-chalcone derivatives were synthesized and tested for antitumor activity against human breast cancer cell lines. The results show the boronic-chalcones are more toxic to breast cancer cells compared to normal breast cells than other known chalcones.