New Generation Taxoids and Taxanes

Paclitaxel and docetaxel have developed into two of the most widely used agents for cancer chemotherapy, with combined sales of roughly 2.8 billion dollars in 2006, however, their lack of tumor-specificity frequently causes the patient to suffer from serious and dangerous side effects. Although they are effective against numerous cancers (e.g. breast, ovary and lung cancers), these usually potent compounds often show little to no efficacy when used to treat melanoma, pancreatic and renal cancers. This resistance to paclitaxel is usually attributed to the presence of the Multi-Drug Resistant (MDR) phenotype, caused by the over-expression of ABC transporters such as the P-glycoprotein (Pgp), an efflux pump responsible for the removal of cytotoxic agents from the interior of the cell.

The new-generation taxoid, SB-T-1214 exhibited high efficiency against colon cancer in vivo, inducing complete regression of drug-resistant colon tumor xenografts in all surviving mice with tumor growth delay up to 201 days [8]. Such promising antitumor activity of SB-T-1214 led us to suggest that this compound can specifically target tumor-specific CSCs by inhibiting some stemness-related signaling pathways and/or promoting their differentiation.

In collaboration with Dr. Galina Botchkina, we have isolated CSCs from various colon cancer cell lines, induced 3-dimensional CSC spheroids and treated these spheriods with SB-T-1214. Treatment of SB-T-1214 led to a nearly-complete inhibition of the stem cell-related genes and significant down-regulation of the pluripotency gene expression in HCT-116, DLD-1 and HT-29 colon CSCs.

β-Lactam Synthon Method for the Synthesis of Taxoids

In 1992, the Ojima group reported the highly efficient semisynthesis of paclitaxel utilizing the beta-lactam synthon method. Coupling of enantiopure beta-lactams to properly derivatized baccatin scaffolds via the Ojima-Holton coupling protocol has allowed the facile synthesis of paclitaxel analogues. Over the past twenty years, our lab has produced a large number of next-generation taxoids, which exhibit marked improvement in cytotoxicity against both drug-sensitive and drug-resistant cancer cell lines.

Enantiopure β-lactams can be synthesized using two methods: (1) ester enolate-imine cyclocondentation using Whitesell’s chiral auxillary; and (2) enzymatic resolution using PS Amano Lipase

β-lactam synthesis using Whitesell’s chiral auxillary

taxoid1

β-lactam synthesis via enzymatic resolution

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Ojima-Holton coupling

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Use of New Generation Taxoids as Warheads

Emerging evidence suggests that a small sub-population of cells within a tumor are responsible for tumor proliferation, patient relapse and metastasis. As these cells exhibit many characteristic phenotypic markers of stem cells, they are referred to as cancer stem cells. Treatment of colonies enriched in cancer stem cells with next-generation taxoid SB-T-1214 showed not only the compound’s ability to kill these cells, but RNA analysis of the living cells showed a marked decrease in expression of many genes related to stemness. This encouraging finding suggests that this compound may be able to promote differentiation of these cells, as well as demonstrating remarkable potency. New generation taxoids are also highly efficacious against paclitaxel-resistant cell lines based on point mutations, pancreatic cancer cell lines and tumor xenografts, and a variety of other drug-sensitive and drug-resistant cell lines, including GI cancer stem cells.

taxoid4I. Ojima et al., J. Med. Chem. 51,3203–3221(2008)

Genomic profiling of altered clonogenic capacity of HCT116 CSCs after SB-T-1214 treatment

New generation taxoid, SB-T-1214 possesses significant activity against CSC-mediated colon cancer spheroids. The data indicates that the previously observed long-term efficacy of SB-T-1214 against drug resistant colon tumors in vivo may be explained by the down-regulation of multiple stem cell-related genes in the tumorigenic cell population, in addition to its known efficacy as a mitotic poison against proliferating cancer cells.

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As seen from the figure above, relatively low concentrations of SB-T-1214 (100 nM-1 μM for 24 or 48 hr) induced dramatic down-regulation of stemness in the majority of stem cell-related genes in all three types of colon cancer cells. It is worthy to note that many of these genes were related to the stem cells self-renewal, regulation of symmetric/asymmetric division and pluripotency. For the efficacy displayed in both bulk and CSC-enriched cells, SB-T-1214 was used as drug warheads for our tumor-targeting drug conjugates.

Botchkina, G.; Zuniga, E. S.; Das, M.; Wang, Y.; Wang, H.; Zhu, S.; Savitt, A. G.; Rowehl, R. A.; Leyfman, Y.; Jingfang, J.; Shroyer, K.; Ojima, I. New-generation taxoid SB-T-1214 inhibits stem cell-related gene expression in 3D cancer spheroids induced by purified colon tumor-initiating cells. Molecular Cancer, 2010, 9, 192.

Taxoid Mechanism of Action

Taxoids are potent antitumor agents which stabilize microtubule polymerization and inhibit the disassembly of the mitotic spindle, stopping chromosome segregation and arresting mitosis in the G2/M phase.

taxoid6Ojima, I., et. al., J. Med. Chem., 2008, 51, 3203-3221

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β-lactam synthesis using Whitesell’schiralauxillary

Department of Chemistry, Stony Brook University, Stony Brook, New York 11794-3400 Phone: (631) 632-7890