Patricia Bonaz-Krause

Bio: Patricia Bonaz-Krause is an academic researcher from University of Southern California. The author has contributed to research in topics: Phosphonate & Diazo. The author has an hindex of 2, co-authored 4 publications receiving 253 citations.

Synthesis, Biological Evaluation, and Quantitative Structure−Activity Relationship Analysis of New Schiff Bases of Hydroxysemicarbazide as Potential Antitumor Agents†

Abstract: Thirty Schiff bases of hydroxysemicarbazide (Ar−CHNNHCONHOH) have been synthesized and tested against L1210 murine leukemia cells. The IC50 values were found to be in a range from 2.7 × 10-6 to 9.4 × 10-4 M. A total of 17 out of the 30 compounds had higher inhibitory activities than hydroxyurea (an anticancer drug currently used for the treatment of melanoma, leukemia, and ovarian cancer) against L1210 cells. Six compounds with IC50 values in micromolar range were 11- to 30-fold more potent than hydroxyurea (IC50 = 8.2 × 10-5 M). The partition coefficient (log P) and ionization constants (pKa) of a model compound [1-(3-trifluoromethylbenzylidene)-4-hydroxysemicarbazide, 1] were measured by the shake-flask method, and the measured log P was used to derive Hansch−Fujita π constant of −CHNNHCONHOH. On the basis of the newly derived π and those of other moieties, the partition coefficients (SlogP) of the other 29 compounds were calculated by the summation of π values. Quantitative structure−activity relations...

Preparation and use of alpha-keto phosphonates

Abstract: Novel phosphonate compounds are provided including a phosphonoglyoxylamide ester, an α-keto phosphonophosphinate ester, a carbonylbisphosphonate analog of a nucleotide, and a diazomethylenebisphosphonate analog of a nucleotide, as well as methods of making synthetically and medically useful α-keto phosphonate compounds.

Oxidative Pathways of α-Diazo Phosphonates

Abstract: We previously reported that α-diazo phosphonoacetate and methylenebisphosphonate alkyl esters (1, 2) could be oxidized to the corresponding α-ketones (3, 4) by, respectively, Rh(II) acetate [Rh2(OAc)4]/propylene oxide and t-butyl hypochlorite/H2O. We report here that t-butyl hypochlorite similarly oxidizes the N,N-dimethyl amide of diethyl phosphonoacetic acid (5) and triethyl α-diazo (phenylphosphinyl)methylphosphonate (6) to the corresponding α-ketones (7, 8). Like 2, 6 is inert to Rh2(OAc)4 (refluxing benzene, excess epoxide, >1 day) but both substrates react quickly and quantitatively when the rhodium ligand is changed from acetate to NHCOC3F7 [Rh2(NHCOC3F7)4], thus providing the first anhydrous and easily scaleable route to analytically pure 4. Rh2(NHCOC3F7)4-mediated epoxide oxidations of 1 (and 5) also proceed under much milder conditions than with Rh2(OAc)4. These more facile oxidations were further accelerated when styrene oxide was used in place of a 1,2-epoxyalkane as the [O] donor, suggesting a change in the rate-determining step. The relative ketone reactivity of 3, 4, and 7 to nucleophiles was estimated by calculation (ab initio, 3-21G*) as 3>4>7. This predicted order of reactivity was found experimentally in a competition experiment (31P NMR) using H2O as the nucleophile.

PREPARATION AND USE OF α-KETO PHOSPHONATES

Abstract: Novel phosphonate compounds are provided including a phosphonoglyoxylamide ester, an α-keto phosphonophosphinate ester, a carbonylbisphosphonate analog of a nucleotide, and a diazomethylenebisphosphonate analog of a nucleotide, as well as methods of making synthetically and medically useful α-keto phosphonate compounds.

Ribonucleotide reductase inhibitors and future drug design.

Abstract: Ribonucleotide reductase (RR) is a multisubunit enzyme responsible for the reduction of ribonucleotides to their corresponding deoxyribonucleotides, which are building blocks for DNA replication and repair. The key role of RR in DNA synthesis and cell growth control has made it an important target for anticancer therapy. Increased RR activity has been associated with malignant transformation and tumor cell growth. Efforts for new RR inhibitors have been made in basic and translational research. In recent years, several RR inhibitors, including Triapine, Gemcitabine, and GTI-2040, have entered clinical trial or application. Furthermore, the discovery of p53R2, a p53-inducible form of the small subunit of RR, raises the interest to develop subunit-specific RR inhibitors for cancer treatment. This review compiles recent studies on (1) the structure, function, and regulation of two forms of RR; (2) the role in tumorigenesis of RR and the effect of RR inhibition in cancer treatment; (3) the classification, mechanisms of action, antitumor activity, and clinical trial and application of new RR inhibitors that have been used in clinical cancer chemotherapy or are being evaluated in clinical trials; (4) novel approaches for future RR inhibitor discovery.

A Series of α-Heterocyclic Carboxaldehyde Thiosemicarbazones Inhibit Topoisomerase IIα Catalytic Activity

Abstract: A series of novel thiosemicarbazone derivatives bearing condensed heterocyclic carboxaldehyde moieties were designed and synthesized. Among them, TSC24 exhibited broad antiproliferative activity in a panel of human tumor cells and suppressed tumor growth in mice. The mechanism research revealed that TSC24 was not only an iron chelator but also a topoisomerase IIalpha catalytic inhibitor. Its inhibition on topoisomerase IIalpha was due to direct interaction with the ATPase domain of topoisomerase IIalpha which led to the block of ATP hydrolysis. Molecular docking predicted that TSC24 might bind at the ATP binding site, which was confirmed by the competitive inhibition assay. These results about the mechanisms involved in the anticancer activities of thiosemicarbazones will aid in the rational design of novel topoisomerase II-targeted drugs and will provide insights into the discovery and development of novel cancer therapeutics based on the dual activity to chelate iron and to inhibit the catalytic activity of topoisomerase IIalpha.