Synthesis Of Taxoid-Porphyrin Conjugates Utilizing Sb-T-1107
Christina Hung, Ed Wu, and Iwao Ojima, Department of Chemistry

The synthesis of novel pro-drugs for chemotherapy is crucial to counter various complications including cell specificity and cellular resistance. This project hoped to achieve a Taxoid-Porphyrin conjugate which would combine the tubulin inhibiting power of the taxoid molecule with the cancer-selectivity of the porphyrin in order to create a drug that results in a two pronged attack against cancerous cells. Taxoids, which were first discovered in the late 1950's in the bark of the Pacific Yew Tree have been shown to have strong cytotoxic abilities by disrupting tubulin formation during cell division, making them the leading drugs used in traditional chemotherapy. Porphyrins (22 pi electron systems) have also played a crucial part in cancer treatment, leading to the rise of photodnamic therapy, a treatment in which a dosage of porphyrins is administered. The porphyrins tend to accumulate in the cancerous cells more readily than in healthy cells, thus, providing a source of cell selectivity. When exposed to a wavelength of visible light, the porphyrin molecule will lead to the formation of singlet oxygen, which will cause severe photodamage to the cell. In order to create Taxoid-Porphyrin conjugates which are theorized to cleave upon entering the cell, a series of amino acids were experimented with in order to form a linking agent between the taxoid and porphyrin molecules. This project explored the use of Beta-Alanine and Glycine as possible coupling mechanisms for the taxoid and porphyrin. On a scale of 200-500 mg, the amino acid was reacted with two equivalences of CBzCl, a protecting reagent. The resultant acid was later reacted with SB-T-1107, a second-generation taxoid, on a scale of 20 mg. Subsequent to the coupling of the acid linker to the taxiod, resulting in the formation of an ester bond, the compound went through hydrogenalysis, which removed the CBz protection, releasing the free amino group. The final reaction between the taxoid/linker and the porphyrin created an amide bond, which was completed in darkened conditions due to the light sensitivity of the compound. Standard procedures for monitoring, workups and purification were used. Proton nmr, Carbon nmr, and High Performance Liquid Chromatography (HPLC) were utilized in order to confirm chemical structure and purity. Samples will be tested for biological activity utilizing a IC50 assay.

This project was supported by Simons Grant 265210 and SBF 265790.

Synthesis Of A Novel Anti-Malarial Baccatin-Quinolyl Acid Conjugate
Christina Hung, Ed Wu and Iwao Ojima, Department of Chemistry
Malaria, a tropical disease cause by plasmodium protozoa has become a widespread disease, affecting over a hundred countries, accounting for millions of deaths annually. The project goal was to synthesize a conjugate between Baccatin and a Quinolyl Acid using glycine as an intermediate which will block heme aggregation, an integral necessity of the parasite. Since the plasmodium protozoa are unable to synthesize crucial amino acids, a host must obtain the acids. The parasite is transmitted to a human by female anopheline mosquito, found most commonly in tropical areas. In the human host, they will enter the liver to reproduce followed by digesting hosts' hemoglobin and excreting wastes hich cause the traditional fever/chill symptoms. Hemoglobin catabolism will occur and release the amino acids the parasite requires while forming a heme aggregate, known as hemozoin. There has been evidence that chloroquine has the ability to disrupt the hemozoin formation. However, the development of chloroquine resistance has yielded a design that attacks microtubule formation. This design can be accomplished with the use of baccatin, which has been shown to have cytotoxic effects due to microtubule disruption. This project explored the use of glycine as an intermediate between 13-Acetyl-Baccatin and (2E)-3-(4-quinolyl) prop-2-enoic acid, a derivative of chloroquine. The intermediate, glycine was first reacted with CBz to provide a protecting group. This will be followed by coupling with the baccatin on a scale of 40 mg. Hydrogenalysis removed the CBz protecting group. The compound was then coupled to the quinolyl acid, yielding the final product. Standard procedures for organic chemistry workups, monitoring and purification were utilized. Proton nmr, Carbon nmr and High Performance Liquid Chromatography (HPLC) were utilized in order to confirm chemical structure and purity. Samples will be tested for biological activity.

This project was funded by SBF 265790 and Simons Grant 265210.

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