The Synthesis of Imidazole Fatty Acid Conjugates as Inhibitors of Apoptosis

Ionizing radiation is known to initiate apoptosis in mammalian cells by causing the transformation of cytochrome c into a peroxidase, which results in the specific peroxidation of the mitochondrial phospholipid cardiolipin. Here we report the design and synthesis of 8 imidazole fatty acid derivatives that bind to the cyt c:CL complex and inhibit the peroxidase activity required for the initiation of apoptosis. We postulate that imidazole acts as a sixth ligand to the haem iron and stops the interaction with H2O2. Two mitochondrially directed analogues (3-hydroxypropyl)triphenylphosphonium esters) of 12-imidazole-stearic acid and 12-imidazole-oleic acid not only were demonstrated to be peroxidase inhibitors in vitro, but were also extraordinarily effective in protecting mice from lethal doses (9 Gy) of ionization radiation. We studied the structure activity relationship to a group of triphenyl phosphonium derivatives containing imidazole at different positions on the fatty acid chain, and observed that the C8-imidazole stearate analogue had marginally better activity than the others. But overall, the structure activity result were remarkable “flat” with all compounds prepared having rather similar inhibitory strength. We also synthesized carnitine mono and di-esters of 12-imidazole fatty acids but full biological data is not yet available for these compounds.

Liberation and Non-Attachment: Arjuna’s Fear in the Bhagavad-Gītā

This thesis takes liberation to be supreme knowledge of the unity underlying the world of multiplicity. This knowledge is always already attained, so all are eternally liberated, but it is unrecognized in ordinary experience. We will look at the Bhagavad-Gītā to consider why this is so. When Arjuna saw Kṛṣṇa’s imperishable Self, he saw all beings standing as one in Kṛṣṇa; thus, he was confronted by supreme knowledge. But he was overwhelmed with fear and confusion and took refuge in blindness. I argue that Arjuna was not prepared to face recognition because he was unpractised in non-attachment. Attached to his subjectivity, he trembled in the face of unity. The supreme goal is standing firm in recognition while living in the world.