Yes / Two approaches for the prediction of which of two vehicles will result in lower toxicity for anticancer agents are presented. Machine-learning models are developed using decision tree, random forest and partial least squares methodologies and statistical evidence is presented to demonstrate that they represent valid models. Separately, a clustering method is presented that allows the ordering of vehicles by the toxicity they show for chemically-related compounds.

No description available.

Chemotherapeutic agents act by targeting rapidly dividing cancer cells. The full extent of their cellular mechanisms, which is essential to balance efficacy and toxicity, is often unclear. In addition, the use of many anticancer drugs is limited by dose-limiting toxicities as well as the development of drug resistance. The work presented in this thesis aims to address the basic biology that underlies these issues through the development and application of chemical genomic tools to probe mechanisms of current and novel anticancer compounds. Chemical genomic screens in the yeast Saccharomyces cerevisiae have been used to successfully identify targets and pathways related to a compound’s mode of action. I applied these screens to examine the mode of action of potential anticancer drugs: a class of platinum-acridine compounds and the apoptosis-inducing compound elesclomol. By analogy to the yeast screens, I developed an RNAi-mediated chemical genomic screen in human cells which has the potential to reveal novel targets and drug mechanisms. This screen was applied to further understand doxorubicin’s mode of action. In parallel with the loss-of-function assays, our lab developed a human ORF overexpression screen in human cells. I applied this gain-of-function screen to identify those genes that, when overexpressed, are toxic to cells. Characterization of such genes that cause toxicity can provide insight into human diseases where gene amplification is prevalent.

Chemotherapeutic agents act by targeting rapidly dividing cancer cells. The full extent of their cellular mechanisms, which is essential to balance efficacy and toxicity, is often unclear. In addition, the use of many anticancer drugs is limited by dose-limiting toxicities as well as the development of drug resistance. The work presented in this thesis aims to address the basic biology that underlies these issues through the development and application of chemical genomic tools to probe mechanisms of current and novel anticancer compounds. Chemical genomic screens in the yeast Saccharomyces cerevisiae have been used to successfully identify targets and pathways related to a compound’s mode of action. I applied these screens to examine the mode of action of potential anticancer drugs: a class of platinum-acridine compounds and the apoptosis-inducing compound elesclomol. By analogy to the yeast screens, I developed an RNAi-mediated chemical genomic screen in human cells which has the potential to reveal novel targets and drug mechanisms. This screen was applied to further understand doxorubicin’s mode of action. In parallel with the loss-of-function assays, our lab developed a human ORF overexpression screen in human cells. I applied this gain-of-function screen to identify those genes that, when overexpressed, are toxic to cells. Characterization of such genes that cause toxicity can provide insight into human diseases where gene amplification is prevalent.

No description available.

Texaphyrins represent the vanguard of experimental anticancer drugs and also symbolize a well-known example of expanded porphyrins, a class of oligopyrrolic macrocycles with tumor localization properties and powerful metal chelating properties. Chapter 1 of this thesis describes the unique structural characteristics of this complex synthetic molecule along with the biological relevance and scientific justifications for studying its anticancer properties and powerful MRI contrast ability. This Chapter also serves to underscore the need to improve further and refine the efficacy of texaphyrins as compounds that may be applied in the struggle against cancer. Chapter 2 details the synthesis of bismuth(III) and lead(II)-texaphyrin complexes that could potentially find use as [alpha]-core emitters for radiotherapy. In principle, porphyrins would ostensibly appear to be ideal ligands for use in radiotherapy due to their tumor-localizing ability. However, Bi(III)- and Pb(II)-porphyrin complexes are extremely rare, most reflecting the vastly challenging synthesis of these compounds as well as their general lack of stability. These limitations provided an incentive for us to use texaphyrins as more versatile ligands to prepare and fully characterize stable bismuth(III) and lead(II) complexes. To be of interest in future medical applications, we needed to prepare these complexes quickly as compared to the relevant time scales set by the half-lives of the isotopes targeted for use in radiotherapy. This goal was successfully realized. As mentioned above, texaphyrin is able to form stable complexes with a large variety of metals particularly in the lanthanide series. Gadolinium(III) complexes of texaphyrin have been studied in considerable detail. Chapter 3 details the synthesis and conjugation methods used to develop a texaphyrin conjugated dual mode nanoparticle contrast agent. This project has been done in collaboration with the group of Prof. Jinwoo Cheon (Yonsei University, Seoul, Korea), who demonstrated fascinating results with the texaphyrin functionalized nanoparticles. Not only do these conjugates act as improved magnetic resonance contrast agents displaying enhanced signals in both the T1 and T2 MRI modes, but also serve to sensitize apoptotic hyperthermia. It is this latter, double effector feature, that has been most extensively studied to date. Chapter 4 of this dissertation describes work done in close collaboration with Dr. Natalie Barkey and Dr. David Morse (Moffitt Cancer Center, Tampa, FL) where a gadolinium texaphyrin complex was developed that is able to target the melanocortin 1 receptor (MC1R) when encapsulated in a micellar system. As detailed in this Chapter, these collaborateurs demonstrated that these gadolinium-texaphyrin micelles are able to target MC1R-expressing xenograft tumors in vivo. This work relied on the supply of a new set of texaphyrin derivatives that were prepared and characterized as part of this dissertation work Chapter 5 of this disseration introduces sapphyrins, another class of expanded porphyrins with tumor selectivity. This project is based on the hypothesis that a direct linkage of sapphyrin with an anticancer agent based on ruthenium(II) could improve the efficacy of both compounds. Since sapphyrins exhibit limited ability to form stable complexes with transition metals, an appended 1,10-phenanthroline unit was chosen as an efficient N-donor aromatic ligand for ruthenium(II). Therefore, extensive synthetic efforts were made to form this sapphyrin-1,10-phenanthroline construct in an effort to stabilize a mixed sapphyrin-metallo-phenanthroline complex. Finally, Chapter 6 of this dissertation demonstrates the author's efforts to synthesize a planar rosarin species. Non-aromatic and non-planar rosarins have been known for over two decades. Through structural modification of the compound, namely through linking of both [Beta] positions on the bipyrrole unit, a new planar rosarin species has been synthesized exhibiting Hückel antiaromaticity. / text

La Cathepsine D (CathD) est une protéase lysosomale surexprimée et sécrétée par de nombreuses tumeurs solides. Cette enzyme favorise la prolifération tumorale et le processus métastatique, faisant d’elle une cible intéressante pour la thérapie anticancéreuse. Il existe un très bon inhibiteur de la CathD, la pepstatine, mais celui-ci traverse trop difficilement la membrane cellulaire pour être actif. C’est pourquoi des vecteurs de pénétration cellulaire, basés sur l’oligomérisation de mimes contraints de dipeptide, ont été développés au laboratoire. De ce travail, un bioconjugué, le JMV4463, a été développé. Composé d’un vecteur AMPA4 (tétramère de l’acide 2-(aminométhyl)phénylacétique), de la pepstatine, et d’une partie hydrophile aidant à la solubilisation du conjugué, ce bioconjugué est capable d’entrer dans les cellules et possède une activité antiproliférative sur différentes lignées de cellules cancéreuses. Partant de ce travail, la synthèse de nouveaux vecteurs potentiels de pénétration cellulaire, oligomères de mimes contraints de dipeptide, a été réalisée. Leur capacité d’internalisation a été établie sous la forme de conjugués avec la pepstatine. Les monomères envisagés étaient des analogues des motifs AMPA et acide (S)-2-(3-amino-4-oxo-3,4-dihydrobenzo[b][1,4]thiazépin-5(2H)-yl)acétique (DBT), motif ayant également montré une importante capacité d’internalisation. Ainsi, des analogues de l’AMPA en série indole, pyrrole et cyclohexane ont été préparés. De plus, la synthèse d’analogues de l’AMPA possédant différentes substitutions a été réalisée, tels que les méta- et para-AMPA, un homologue inférieur ou les 4,5-diméthoxy-, 4,5-dihydroxy- et 4-bromo-AMPA. Un analogue en série benzodiazépine du DBT a également été étudié. Tous les vecteurs correspondants sont capables d’internaliser la pepstatine dans les cellules mais, de façon surprenante, aucun des conjugués n’a montré d’activité anti-proliférative, indiquant un rôle essentiel du vecteur AMPA4. Une étude des relations structure / activité du JMV4463 a confirmé que le vecteur AMPA4 possédait un mode d’action unique mais celui-ci n’a pu être identifié à ce jour. Dans cette étude, il a également été montré qu’il était possible de simplifier la structure de la pepstatine, en remplaçant un de ses motifs statine par un motif gamma-alanine, permettant un coût de production réduit. Enfin, une étude in vivo sur un modèle xénogreffé de souris a montré un fort potentiel anti-tumoral du conjugué JMV4463. / Cathepsin D (CathD) is an overexpressed lysosomal protease secreted by several solid tumors. This enzyme is involved in tumor proliferation and metastasis, which makes it a promising target for cancer therapy. There exists a potent CathD inhibitor called Pepstatin, but it presents a too poor ability to cross the plasmic membrane in order to be active. To overcome this drawback, the development of cell penetrating vectors based on the oligomerization of constrained dipeptide mimetics has been undertaken in our lab. From this work, the bioconjugate JMV4463 has been developed. This bioconjugate is made of an AMPA4 (2-(aminomethyl)phenylacetic acid) vector, the pepstatin and a hydrophilic part which increases its solubility. This bioconjugate is able to penetrate the cells and has an antiproliferative effect on different cancer cell lines. Based on this work, synthesis of new potential cell penetrating vectors, oligomers of constrained dipeptide mimetics, was performed. Their internalization ability was established as their conjugate with pepstatin. We developed analogues of AMPA scaffold and (S)-2-(3-amino-4-oxo-3,4-dihydrobenzo[b][1,4]thiazépin-5(2H)-yl)acetic acid (DBT), which showed an important internalization ability. Thus, AMPA derivatives in indole, pyrrole and cyclohexane series were prepared. Furthermore, the synthesis of AMPA analogues having different substitutions on its aromatic part was performed, such as meta- and para- AMPA, an inferior homologue or 4,5-dimethoxy-, 4,5-dihydroxy- and 4-bromo-AMPA. An analogue of DBT in the benzodiazepin series has also been studied. All the corresponding vectors were able to internalize the pepstatin into the cells. Surprisingly, none of the conjugates showed an anti-proliferative activity, indicating the essential role of the AMPA vector. A structure/activity relationships study was performed for JMV4463. The obtained results confirmed that the AMPA vector has a unique mode of action that has not been identified yet. Furthermore, it has been demonstrated that it was possible to simplify the pepstatin structure by replacing one of its statin residues by a gamma alanine, which allows decreasing the production cost. Finally, an in vivo study on a xenografted mouse model showed a high anti-tumour potential for the JMV4463 conjugate.

yes / A series of ruthenium and iridium complexes have been synthesized and characterized with 20 novel crystal structures discussed. The library of β-ketoiminato complexes has been shown to be active against MCF-7 (human breast carcinoma), HT-29 (human colon carcinoma), A2780 (human ovarian carcinoma), and A2780cis (cisplatin-resistant human ovarian carcinoma) cell lines, with selected complexes’ being more than three times as active as cisplatin against the A2780cis cell line. Selected complexes were also tested against the noncancerous ARPE-19 (retinal pigment epithelial cells) cell line, in order to evaluate the complexes selectivity for cancer cells. Complexes have also been shown to be highly active under hypoxic conditions, with the activities of some complexes increasing with a decrease in O2 concentration. The enzyme thioredoxin reductase is overexpressed in cancer cells, and complexes reported herein have the advantage of inhibiting this enzyme, with IC50 values measured in the nanomolar range. The anticancer activity of these complexes was further investigated to determine whether activity is due to effects on cellular growth or cell survival. The complexes were found to induce significant levels of cancer cell death by apoptosis with levels induced correlating closely with activity in chemosensitivity studies. As a possible cause of cell death, the ability of the complexes to induce damage to cellular DNA was also assessed. The complexes failed to induce double-strand DNA breaks or DNA cross-linking but induced significant levels of single-strand DNA breaks, indicating a mechanism of action different from that of cisplatin. / Lord RM, Hebden AJ, Pask CM, Henderson IR, Allison SJ, Shepherd SL, Phillips RM, McGowan PC

yes / Group IV metal complexes have previously shown promise as novel anticancer agents. Here, we discuss the mechanistic and cytotoxic nature of a series of group IV b-diketonate coordination complexes. Clear evidence that the ligands are exchangeable on the metal centre and that the b-diketonate ligands can act as potential drug delivery vehicles of the group IV metal ions was obtained. When evaluated for the cytotoxicity against human colon adenocarcinoma (HT-29) and human breast adenocarcinoma (MCF-7) cell lines, a general trend of decreasing potency down the group IV metals was observed. The most promising results obtained were for the hafnium complexes, with the tris diphenyl b-diketonate hafnium complex exhibiting IC50 values of 4.9 0.9 mm and 3.2 0.3 mm against HT-29 and MCF-7, respectively, which are comparable with the activity of cisplatin against the same cell lines. This tri b-diketonate hafnium complex is the first to show potent in vitro cytotoxic activity. The results reported show that ligand design has a significant effect on the cytotoxic potential of the complexes, and that these group IV complexes warrant further evaluation as novel metal-containing anticancer agents.

yes / Condensation of a pyridyl-2-carbaldehyde derivative with 2-(bromoethyl)amine hydrobromide gave tetracyclic pyrido[1,2-a]pyrido[1’,2’:3,4]imidazo-[2,1-c]-6,7-dihydropyrazinium dications in excellent yields. Crystal structures and NOE data demonstrated the helical character of the dications, the dihedral angles between the two pyrido groups ranging from 28–458. An intermediate in the synthesis was also characterized. A much brighter emission compared to literature helicenes has been found, with quantum yields as high as 60% in the range of l=460– 600 nm. Preliminary cytotoxicity studies against HT-29 cancer cells demonstrated moderate-to-good activity, with IC50 values 12–30x that of cisplatin.