Medicinal Chemistry and Chemical Biology of New Generation Taxane Antitumor Agents

Ojima, Iwao; Geney, Raphaël; Ungureanu, Ioana; Li, Dansu

doi:10.1080/15216540212658

Cited by 23 publications

(18 citation statements)

References 27 publications

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“…Utilizing the substrate plasticity shown with previously characterized paclitaxel acyl transferases, transgenic organisms offer the potential to facilitate novel functional group substitutions through biological mechanisms, rather than the chemical mechanisms generally associated with combinatorial chemistry [87,89,90]. In addition to further evaluation of these pre-existing substitutions on paclitaxel anti-mitotic activity, the substitution of novel functional groups has already been achieved through chemical processes, and has been shown to have advantageous effects on the solubility of paclitaxel or the degree of anti-mitotic activity [112,113]. Utilizing the same transgenic E. coli expressing a recombinant DBAT, modified baccatin III containing propionyl and n-butyryl has been produced, providing an avenue by which second-generation taxoids may be developed [80].…”

Section: Metabolic Engineering Of Organisms To Produce Taxoidsmentioning

confidence: 99%

Advancements in the Understanding of Paclitaxel Metabolism in Tissue Culture

Vongpaseuth¹,

Roberts

2007

CPB

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Paclitaxel is a potent chemotherapeutic agent approved in the treatment of a variety of cancers, and under evaluation for the treatment of Alzheimer's and heart disease. Originally isolated from Taxus brevifolia, this highly substituted ring diterpenoid belongs to a family of plant secondary metabolites known as taxoids. Paclitaxel is currently supplied through both a semi-synthetic process and plant cell culture. Taxus spp. cell culture offers the potential to produce large amounts of paclitaxel and related taxoids, although variability in accumulation and low yields represent key limitations. Thus, intense efforts have been put forth towards understanding Taxus spp. metabolism to increase paclitaxel accumulation in cell culture. While elicitation and environmental optimization have provided some success in increasing paclitaxel accumulation in vitro, understanding metabolism of paclitaxel on the molecular level is essential for process optimization. Utilizing direct and indirect molecular techniques, a further understanding of paclitaxel biosynthesis has been gained, though knowledge into other aspects of paclitaxel global metabolism, such as regulation, transport, and degradation is lacking. Taxus spp. cell cultures are highly heterogeneous, displaying significant cell-cell variability in growth and paclitaxel accumulation. Information gathered on culture subpopulations as well as putative transcriptional bottlenecks in paclitaxel biosynthesis, coupled with successful transformation of Taxus spp. will allow for the targeted metabolic engineering of Taxus spp. or other model organisms for paclitaxel accumulation to ensure future supply of this important pharmaceutical.

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Section: Metabolic Engineering Of Organisms To Produce Taxoidsmentioning

confidence: 99%

Advancements in the Understanding of Paclitaxel Metabolism in Tissue Culture

Vongpaseuth¹,

Roberts

2007

CPB

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“…3) [72][73][74][75][76][77][78][79]. Most of these taxoids exhibited one order of magnitude higher potency than that of paclitaxel against drug-sensitive cancer cell lines, and some of these taxoids showed 2-3 orders of magnitude higher potency than that of paclitaxel against drug-resistant cell lines, which makes them highly promising clinical candidates for cancer chemotherapy.…”

Section: Second Generation Taxoids-mab Conju-gatesmentioning

confidence: 97%

Tumor Specific Novel Taxoid-Monoclonal Antibody Conjugates

Wu¹,

Ojima²

2004

CMC

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The basic principle of the targeted delivery approach is that the conjugation of a drug to a tumor-specific molecule renders the drug inactive until it reaches the target site. Monoclonal antibodies (mAbs), which have shown high binding specificity for tumor-specific antigens, could be used as targeting agents. Paclitaxel has brought significant impact on the current cancer chemotherapy, but seriously suffers from the lack of tumor specificity. A series of paclitaxel-monoclonal antibody conjugates via C-2' ester linkage were reported. Taking into account the fact that the cytotoxicity of paclitaxel is not good enough and thus not applicable to this target delivery prodrug approach, new taxoids bearing methyldisulfanyl(alkanoyl) groups were designed, synthesized, and their activities evaluated. A highly cytotoxic C-10 methyldisulfanyl-propanoyl taxoid, was conjugated to monoclonal antibodies recognizing the epidermal growth factor receptor (EGFR). These conjugates were shown to possess remarkable target-specific antitumor activity in vivo against EGFR-expressing A431 tumor xenografts in SCID mice, resulting in complete inhibition of tumor growth in all the treated mice without any noticeable toxicity to the animals.

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“…It is also a stabiliser of microtubules and is cytotoxic against several human cells. It is used in the treatment of locally advanced metastatic breast cancer and non-small-cell lung cancer [152][153][154][155][156] (Fig. 9).…”

Section: Paclitaxel (Taxol ® ) and Docetaxel (Taxotere ® )mentioning

confidence: 99%

Natural products as leads to anticancer drugs

2007

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Throughout history, natural products have afforded a rich source of compounds that have found many applications in the fields of medicine, pharmacy and biology. Within the sphere of cancer, a number of important new commercialised drugs have been obtained from natural sources, by structural modification of natural compounds, or by the synthesis of new compounds, designed following a natural compound as model. The search for improved cytotoxic agents continues to be an important line in the discovery of modern anticancer drugs. The huge structural diversity of natural compounds and their bioactivity potential have meant that several products isolated from plants, marine flora and microorganisms can serve as "lead" compounds for improvement of their therapeutic potential by molecular modification. Additionally, semisynthesis processes of new compounds, obtained by molecular modification of the functional groups of lead compounds, are able to generate structural analogues with greater pharmacological activity and with fewer side effects. These processes, complemented with high-throughput screening protocols, combinatorial chemistry, computational chemistry and bioinformatics are able to afford compounds that are far more efficient than those currently used in clinical practice. Combinatorial biosynthesis is also applied for the modification of natural microbial products. Likewise, advances in genomics and the advent of biotechnology have improved both the discovery and production of new natural compounds.

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Medicinal Chemistry and Chemical Biology of New Generation Taxane Antitumor Agents

Abstract: Summary P-glycoprotein (P-GP)-based multidrug resistance (MDR) and

Cited by 23 publications

References 27 publications

Advancements in the Understanding of Paclitaxel Metabolism in Tissue Culture

Advancements in the Understanding of Paclitaxel Metabolism in Tissue Culture

Tumor Specific Novel Taxoid-Monoclonal Antibody Conjugates

Natural products as leads to anticancer drugs

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