Synthesis of a Novel RAS Farnesyl Protein Transferase Inhibitor

Mutant RAS proteins are associated with 30% of all human cancers. Unregulated cell growth caused by mutant RAS proteins can be prevented by RAS farnesyl protein transferase (FPTase) inhibitors. A novel FPTase inhibitor has been synthesized incorporating a modified farnesyl “tail” and a customized diphosphate “head”. It is anticipated that the modified “tail”, incorporating a phenyl substituent, will bind more tightly to FPTase due to nonbonding interactions between the aromatic ring and ten aromatic amino acid residues that line the enzyme active site. The altered polar “head”, designed from L-aspartic acid, has already been shown to mimic the natural substrate’s diphosphate moiety. It is anticipated that the bioactivity of the novel compound presented in this research will illustrate the relevance of modifications to the farnesyl “tail” in the design of farnesyl diphosphate mimetics

The Case of the Missing Music: An Outreach Activity Sparks Interest in Science and Density

From Scooby Doo and Nancy Drew to the countless other detectives that fill children’s bookshelves and television programs, it is clear that children are fascinated with solving crimes. As a result, a chemistry professor who performs outreach activities at local elementary schools exploited this interest in mysteries as a method to spark curiosity in science. This was accomplished through the development of an outreach activity in which students solve a mystery using density and fingerprint analysis

The Design and Synthesis of Novel Goniothalamin Analogues

Every two minues a woman in the United States is diagnosed with breast cancer. In recent years, one method to identify potential chemotherapeutic agents has been the mass screening of natural products of cytotoxicity. One compound discovered in this manner was goniothalamin. Gonothalamin was isolated from the dried stem bark of the plant Goniothalamus sesuipedalis and exhibits cell specific anticancer activity against breast cancer. Goniothalamin has been extensively studies and a large number of synthetic analogues have been prepared in an attempt to determine the structural features necessary for bioactivity. These studies have focused primarily on the manipulation of goniothalmin\u27s styryl substituent. The focus of this research is on the lactone core of goniothalamin. Analogues have been prepared that replace the lactone ring with lactam. It is anticipated that alteration of the lactam nitrogen substituent will potentially lead to analogues with better bioavailability and reactivity than the natural product

Chemotherapeutic Drug Design: An Efficient Synthesis of 4-Substituted Alpha-Methylene-Gamma-Lactones

Sesquiterpene lactones are plant-derived compounds that have been shown to possess significant activity against inflammation and cancer. Comparative studies of sesquiterpene lactone structure and tumor cytotoxicity indicate that the presence of an α-methylene-γ-lactone moiety is necessary for bioactivity. This observation has led to the hypothesis that simple compounds containing this pharmacophore may also exhibit similar anti-cancer properties. To test this theory, an efficient synthesis of 4-substituted α-methylene-γ-lactone has been developed. The model compound in this study, α-methylene-γ-dodecalactone, has been prepared from commercially available 1-decene in six steps. The synthesis features a nucleophilic epoxide ring-opening reaction followed by an intramolecular cyclization to prepare a key lactone intermediate. The described sequence should provide access to a large number of 4-substituted α-methylene-γ-lactone analogues that can be used to better understand the role alkyl substituents play in the bioactivity of this class of compounds

The Design and Synthesis of Novel Chaetomellic Acid A Analogues

Chaetomellic acid A is an alkyl dicarboxylic acid isolated from the fermentation of Chaetomella acutiseta. Chaetomellic acid A has been shown to be a potent, highly specific inhibitor of RAS farnesyl protein transferase (FPTase). The association between RAS proteins and cancer has made chaetomellic acd A a potential chemotherapeutic agent. Two novel chaetomellic acid A analogues have been prepared that incorporate aromoatic rings in the alkyl tail. It is anticipated that these compounds will bind more tightly to the FPTase active site than the natural product due to intermolecular interactions between the aromatic rings in the tail and the aromatic amino acid residues that have been shown to line the enzyme pocket

Chemotherapeutic Agents from Natural Product Templates: The Design and Synthesis of Novel Indanone Analogues

Coumarin is a natural product found in many plants. Recently, simple coumarin analogues containing an α-methylene functional group have been synthesized and shown to exhibit cytotoxicity against cancer cell lines. The α,β-unsaturated carbonyl found in these analogues is thought to be responsible for their bioactivity. Other natural products containing this functional group have been shown to react with intracellular thiols causing tumor growth suppression. Using these analogues as a template, two new compounds have been designed that feature a novel α-methylene indanone structural framework. Since ketones are better electrophiles that esters, it is hypothesized that these analogues will react more rapidly with thiols that their coumarin counterparts. The two α-methylene indanone analogues, one incorporating an isopropyl and the other an n-butyl substituent, have been prepared in five and seven steps respectively. Both synthetic sequences feature a 1,4-organometallic addition reaction, in intramolecular Friedel-Crafts acylation, and an α-methylenation of the key inadone intermediates

Design and Synthesis of a Potential Chemotherapeutic Agent Using Goniothalamin as a Natural Product Template

Goniothalamin, a natural product extracted from the tree bark of the Goniothalamus genus, has been shown to induce apoptosis in cancer cells. It is hypothesized that goniothalamin\u27s biological activity is due to its ability to react with thiols. Goniothalamin has been shown to decrease levels of glutathione, a natural antioxidant, found in cancer cells. This causes a redox imbalance, which ultimately leads to cell death. Thiol-reactive compounds, like goniothalamin, have also been shown to inhibit nuclear factor-κB (NF-κB). NF-κB is a transcription factor that has been implicated in unregulated cell growth. Through a nine step sequence, a novle analogue of goniothalamin has been prepared that replaces the lactone core of the nature product with a cyclohexenone. The synthetic sequence features a unique enol ether protection of beta-diketone which allows facile preparation of the desired analogue. It is anticipated that the novel goniothalamin derivative will demonstrate increaed cytotoxicity against cancer cells

The Design and Synthesis of Farnesyl Tail Analogues Incorporating Aromatic Rings: A Comparison of Wittig and Grignard Reaction Sequences

Mutant RAS proteins have been linked to over 30 of all human cancers. It has been shown that mutant RAS proteins that cannot be farnesylated do not induce malignant transformation. Therefore, farnesyl protein transferase (FPTase) inhibitors have become attractive targets as potential chemotherapeutic agents. Two farnesyl tail analogues have been prepared that incorporate aromatic rings. One of the compounds, trans-9-phenyl-8-nonen-1-ol, could only be prepared pure using a Grignard reaction sequence. This sequence is compared to the initially attempted Wittig reaction sequence that results in an inseparable mixture of cis/trans isomers. It is anticipated thatwhen coupled with poal diphosphate head mimetics, the tails prepared in this pper will help illuminate the importance of nonbonding interactions in the binding of farnesyl pyrophosphate analogues to the FPTase enzyme active site

Design and Synthesis of a Novel Alpha-Methylene Lactone Chemotherapeutic Agent

Goniothalamin, a natural product isolated from the dried stem bark of Malaysian plants of the genus Goniothalamus, has been shown to induce apoptosis in cancer cells. The bioactivity of this molecule is though to be due to its ability to react with thiols. One mechanism involves its reaction with glutathione, a natural antioxidant found in all cells. Using a four step synthetic sequence, a novel gamma-lactone analogue of goniothalamin has been prepared that replaces the endocylic double bond in goniothalamin\u27s lactone core with an exocyclic double bond. It is anticipated that this alteration will allow the compound to react more rapidly with thiols and therefore increase its cytotoxicity towards cancer cells

Dysmorphometrics: the modelling of morphological abnormalities

<p>Abstract</p> <p>Background</p> <p>The study of typical morphological variations using quantitative, morphometric descriptors has always interested biologists in general. However, unusual examples of form, such as abnormalities are often encountered in biomedical sciences. Despite the long history of morphometrics, the means to identify and quantify such unusual form differences remains limited.</p> <p>Methods</p> <p>A theoretical concept, called dysmorphometrics, is introduced augmenting current geometric morphometrics with a focus on identifying and modelling form abnormalities. Dysmorphometrics applies the paradigm of detecting form differences as outliers compared to an appropriate norm. To achieve this, the likelihood formulation of landmark superimpositions is extended with outlier processes explicitly introducing a latent variable coding for abnormalities. A tractable solution to this augmented superimposition problem is obtained using Expectation-Maximization. The topography of detected abnormalities is encoded in a dysmorphogram.</p> <p>Results</p> <p>We demonstrate the use of dysmorphometrics to measure abrupt changes in time, asymmetry and discordancy in a set of human faces presenting with facial abnormalities.</p> <p>Conclusion</p> <p>The results clearly illustrate the unique power to reveal unusual form differences given only normative data with clear applications in both biomedical practice & research.</p