Testamentary Freedom Vs. the Natural Right to Inherit: The Misuse of No-Contest Clauses As Disinheritance Devices

Testamentary freedom is the bedrock of inheritance law. The freedom is curbed in some respects in order to allow spouses and other groups access to an estate. However, there is no restriction on a parent\u27s ability to disinherit their children. This note is a critique of the permitted disinheritance of children in the name of testamentary freedom. According to John Locke, the right to inherit emanates from natural law and should be recognized as such. Through forced heirship, as recognized in other modern nations, the U.S. can respect the natural right of children to inherit and leave room for testamentary freedom. Forced heirship can alleviate the unjustifiable harms imposed on adult children and preserve familial relationships after the death of a parent. Until forced heirship is recognized, disinherited beneficiaries seeking access to an estate must navigate around laws governing no-contest clauses, devices that are often used to disinherit children. In California, that path is through its probable cause exception to no-contest clauses and the intentional interference with an expected inheritance tort. Until forced heirship is recognized, courts should not permit no-contest clauses to effectuate disinheritance but restrict enforcement of no-contest clauses for protecting estates from complicated ownership disputes and outsiders attempting to gain access to an estate

Novel trifluoromethylated 9-amino-3,4-dihydroacridin-1(2H)-ones act as covalent poisons of human topoisomerase IIα

A number of topoisomerase II-targeted anticancer drugs, including amsacrine, utilize an acridine or related aromatic core as a scaffold. Therefore, to further explore the potential of acridine-related compounds to act as topoisomerase II poisons, we synthesized a series of novel trifluoromethylated 9-amino-3,4-dihydroacridin-1(2H)-one derivatives and examined their ability to enhance DNA cleavage mediated by human topoisomerase IIα. Derivatives containing a H, Cl, F, and Br at C7 enhanced enzyme-mediated double-stranded DNA cleavage ∼5.5- to 8.5-fold over baseline, but were less potent than amsacrine. The inclusion of an amino group at C9 was critical for activity. The compounds lost their activity against topoisomerase IIα in the presence of a reducing agent, displayed no activity against the catalytic core of topoisomerase IIα, and inhibited DNA cleavage when incubated with the enzyme prior to the addition of DNA. These findings strongly suggest that the compounds act as covalent, rather than interfacial, topoisomerase II poisons

The Synthesis of Novel Fluorinated 9-Amino Acridones as Potential Topoisomerase IIα Poisons

Our group is studying fluorinated acridone derivatives for the first time, for their potential as topoisomerase IIα poisons. Topoisomerases are nuclear enzymes, that are needed for replication, transcription, and recombination. Specifically, they are responsible for relaxing supercoiled DNA by removing knots and tangles prior to the above processes. Although there are two isoforms of topoisomerases (Topo I and Topo II), we are focusing on compounds that could act as topoisomerase poisons, which are among the most widely prescribed anticancer drugs. The proto-type drugs include amsacrine and etoposide. Our hypothesis is that small acridone molecules having a trifluoromethyl group on the eastern cyclohexane ring will enhance DNA cleavage and act as a topoisomerase poison. These acridone derivatives are structurally similar to amsacrine. Our preliminary data have demonstrated that 9-amino-7-chloro-3-trifluoromethylacridone is a topoisomerase IIα poison. We have synthesized derivatives with substituents on the leftmost aromatic ring, such as H, Cl, F, 4-Me, Br, and Nitro group. The analysis of the potential inhibitors were tested at a 20µM concentration and the fluorine derivative proved to be most active following its halogen counterparts and the nitro group. Though the unsubstituted and methyl species fell short, activity was present. There are two types of interactions that can lead to inhibition of the enzyme: covalent and noncovalent. Our drug interacts with the enzyme covalently. All compounds were characterized by H1NMR, C13NMR, FTIR, and MelTempII apparatus. Enzyme studies were conducted by drug-DNA-enzyme assay/gel electrophoresis and quantified by an AlphaImager from Alpha Innotech, through collaboration with the Osheroff group at Vanderbilt University School of Medicine

Novel trifluoromethylated 9-amino-3,4-dihydroacridin-1(2H)-ones act as covalent poisons of human topoisomerase IIα

A number of topoisomerase II-targeted anticancer drugs, including amsacrine, utilize an acridine or related aromatic core as a scaffold. Therefore, to further explore the potential of acridine-related compounds to act as topoisomerase II poisons, we synthesized a series of novel trifluoromethylated 9-amino-3,4-dihydroacridin-1(2H)-one derivatives and examined their ability to enhance DNA cleavage mediated by human topoisomerase IIα. Derivatives containing a H, Cl, F, and Br at C7 enhanced enzyme-mediated double-stranded DNA cleavage ~5.5- to 8.5-fold over baseline, but were less potent than amsacrine. The inclusion of an amino group at C9 was critical for activity. The compounds lost their activity against topoisomerase IIα in the presence of a reducing agent, displayed no activity against the catalytic core of topoisomerase IIα, and inhibited DNA cleavage when incubated with the enzyme prior to the addition of DNA. These findings strongly suggest that the compounds act as covalent, rather than interfacial, topoisomerase II poisons