The relationship between the molecular structure of natural acetogenins and their inhibitory activities which affect DNA polymerase, DNA topoisomerase and human cancer cell growth

Abstract

Abstract. acetogenins from the annonaceous plant are a fatty acid-derived natural product. chemically synthesized natural acetogenins, such as mucocin (compound 1), jimenezin (compound 2), muconin (compound 4), pyranicin (compound 5) and pyragonicin (compound 6) were investigated. concomitantly, 19-epi jimenezin (compound 3), 10-epi pyragonicin (compound 7) and a γ-lactone (compound 8), which is estimated to be a biosynthetic precursor of acetogenins, were synthesized and investigated. compounds 5 and 6 strongly inhibited, and compound 7 moderately inhibited the activities of mammalian dna polymerases (pols), such as replicative pol α and repair/recombination-related pol β and λ, and also inhibited human dna topoisomerase (topos) i and ii activities. On the other hand, compounds 1-4 and 8 did not influence the activities of any pols and topos. Compound 5 was the strongest inhibitor of the pols and topos tested, and the ic 50 values were 5.0-9.6 µm, respectively. these compounds also suppressed human cancer cell growth with almost the same tendency as the inhibition of pols and topos. compound 5 was the strongest suppressor of the proliferation of the promyelocytic leukemia cell line, hl-60, in human cancer cell lines tested with an ld 50 value of 9.4 µm, and arrested the cells at G1 phases, indicating that it blocks dna replication by inhibiting the activity of pols rather than topos. this compound also induced cell apoptosis. the relationship between the three-dimensional molecular structure of acetogenins and these inhibitory activities is discussed. the results suggested that compound 5 is a lead compound of potentially useful cancer chemotherapy agents.

The Role of Avocados in Complementary and Transitional Feeding

“…In adults, both phytosterols and PFA have been shown to support a healthy inflammatory response [ 25 ]. Lipophilic acetogenins in avocados [ 92 ] are a group of antioxidants that are synthesized from fatty acid precursors that have promise for their anti-proliferative and apoptotic effects on cancer cells [ 101 , 102 , 103 ]. The amino-acid based antioxidant glutathione, also in avocados in higher concentration (8.4 mg/30 g) that any other fruit [ 104 ], is involved in immune function, lipid metabolism, detoxification, and several aspects of cellular defense and replication [ 105 ].…”

Natural Products, Synthetic and Non-Nucleoside Compounds as Inhibitors of Enzymes Related to DNA: Update 2013

“…These compounds also suppressed human cancer cell growth with almost the same tendency than the inhibition of pols and topos. Compound 44 was also the strongest suppressor of the proliferation of the HL-60 promyelocytic leukemia cell line with an LD value of 9.4 µM, and arrested the cells at G1 phases, indicating that it blocks DNA replication by inhibiting the activity of pols rather than topos [30].…”