Novel derivatives of spirohydantoin induce growth inhibition followed by apoptosis in leukemia cells

Hydantoin derivatives possess a variety of biochemical and pharmacological properties and consequently are used to treat many human diseases. However, there are only few studies focusing on their potential as cancer therapeutic agents. In the present study, we have examined anticancer properties of two novel spirohydantoin compounds, 8-(3,4-difluorobenzyl)-1'-(pent-4-enyl)-8-azaspiro[bicyclo[3.2.1] octane-3,4'-imidazolidine]-2',5'-dione (DFH) and 8-(3,4-dichlorobenzyl)-1'-(pent-4-enyl)-8-azaspiro[bicyclo[3.2.1]octane-3,4'-imidazolidine]-2',5'-dione (DCH). Both the compounds exhibited dose- and time-dependent cytotoxic effect on human leukemic cell lines, K562, Reh, CEM and 8ES. Incorporation of tritiated thymidine ([H-3) thymidine) in conjunction with cell cycle analysis suggested that DFH and DCH inhibited the growth of leukemic cells. Downregulation of PCNA and p-histone H3 further confirm that the growth inhibition could be at the level of DNA replication. Flow cytometric analysis indicated the accumulation of cells at subG1 phase suggesting induction of apoptosis, which was further confirmed and quantified both by fluorescence-activated cell sorting (FACS) and confocal microscopy following annexin V-FITC/propidium iodide (PI) staining. Mechanistically, our data support the induction of apoptosis by activation of the mitochondrial pathway. Results supporting such a model include, elevated levels of p53, and BAD, decreased level of BCL2, activation and cleavage of caspase 9, activation of procaspase 3, poly (ADP-ribosyl) polymerase (PARP) cleavage, downregulation of Ku70, Ku80 and DNA fragmentation. Based on these results we discuss the mechanism of apoptosis induced by DFH and its implications in leukemia therapy. (C) 2008 Elsevier Inc. All rights reserved.

Synthesis of 2-(5-((5-(4-chlorophenyl)furan 2-yl)methylene)-4-oxo-2-thioxo-thiazolidi n-3-yl)acetic acid derivatives and evaluation of their cytotoxicity and induction of apoptosis in human leukemia cells

In order to explore the anticancer effect associated with the thiazolidinone framework, several 2-(5-((5-(4-chlorophenyl)furan-2-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid derivatives 5(a-1) were synthesized. Variation in the functional group at C-terminal of the thiazolidinone led to set of compounds bearing amide moiety. Their chemical structures were confirmed by H-1 NMR, IR and Mass Spectra analysis. These thiazolidinone compounds containing furan moiety exhibits moderate to strong antiproliferative activity in a cell cycle stage-dependent and dose dependent manner in two different human leukemia cell lines. The importance of the electron donating groups on thiazolidinone moiety was confirmed by MTT and Trypan blue assays and it was concluded that the 4th position of the substituted aryl ring plays a dominant role for its anticancer property. Among the synthesized compounds, 5e and 5f have shown potent anticancer activity on both the cell lines tested. To rationalize the role of electron donating group in the induction of cytotoxicity we have chosen two molecules (5e and 5k) having different electron donating group at different positions. LDH assay, Flow cytometric analysis and DNA fragmentation suggest that 5e is more cytotoxic and able to induce the apoptosis. (C) 2009 Elsevier Ltd. All rights reserved.

Synthesis and in vitro cytotoxic evaluation of novel diazaspiro bicyclo hydantoin derivatives in human leukemia cells: A SAR study

To study the structure activity relationship (SAR) on the cytotoxic activity and probe the structural requirement for the potent antitumor activity, a series of novel diazaspiro bicyclo hydantoin derivatives were designed and synthesized. Their structures were confirmed by H-1 NMR, LCMS and IR analyses. The antiproliferative effect of these compounds were determined against human leukemia, K562 (chronic myelogenous leukemia) and CEM (T-cell leukemia) cells using trypan blue and MTT assay, and the SAR associated with the position of N-terminal substituents in diazaspiro bicyclo hydantoin have also been discussed. It has been observed that these compounds displayed strong, moderate and weak cytotoxic activities. Interestingly, compounds having electron withdrawing groups at third and fourth position of the phenyl ring displayed selectively cytotoxic activities to both the cell lines tested with IC50 value lower than 50 mu M. In addition, the cytotoxic activities of the compounds 7(a-o) bearing the substituents at N-3 position of diazaspiro bicyclo hydantoin increases in the order alkene > ester > ether and plays an important role in determining their antitumor activities. The position and number of substituents in benzyl group attached to N-8 of diazaspiro bicyclo hydantoin nucleus interacted selectively with specific targets leading to the difference of biochemical and pharmacological effects.

An (O)over-tilde(mn) Gomory-Hu Tree Construction Algorithm for Unweighted Graphs

We present a fast algorithm for computing a Gomory-Hu tree or cut tree for an unweighted undirected graph G = (V, E). The expected running time of our algorithm is (O) over tilde (mc) where vertical bar E vertical bar = m and c is the maximum u-v edge connectivity, where u, v is an element of V. When the input graph is also simple (i.e., it has no parallel edges), then the u-v edge connectivity for each pair of vertices u and v is at most n - 1; so the expected run-ning time of our algorithm for simple unweighted graphs is (O) over tilde (mn). All the algorithms currently known for constructing a Gomory-Hu tree [8, 9] use n - 1 minimum s-t cut (i.e., max flow) subroutines. This in conjunction with the current fastest (O) over tilde (n(20/9)) max flow algorithm due to Karger and Levine[11] yields the current best running time of (O) over tilde (n(20/9)n) for Gomory-Hu tree construction on simple unweighted graphs with m edges and n vertices. Thus we present the first (O) over tilde (mn) algorithm for constructing a Gomory-Hu tree for simple unweighted graphs. We do not use a max flow subroutine here; we present an efficient tree packing algorithm for computing Steiner edge connectivity and use this algorithm as our main subroutine. The advantage in using a tree packing algorithm for constructing a Gomory-Hu tree is that the work done in computing a minimum Steiner cut for a Steiner set S subset of V can be reused for computing a minimum Steiner cut for certain Steiner sets S' subset of S.

Synthesis and biological evaluation of novel 1-(4-methoxyphenethyl)-1H-benzimidazole-5-carboxylic acid derivatives and their precursors as antileukemic agents

We report here the synthesis and preliminary evaluation of novel 1-(4-methoxyphenethyl)-1H-benzimidazole-5-carboxylic acid derivatives 6(a–k) and their precursors 5(a–k) as potential chemotherapeutic agents. In each case, the structures of the compounds were determined by FTIR, 1H NMR and mass spectroscopy. Among the synthesized molecules, methyl 1-(4-methoxyphenethyl)-2-(4-fluoro-3-nitrophenyl)-1H-benzimidazole-5-carboxylate (5a) induced maximum cell death in leukemic cells with an IC50 value of 3 μM. Using FACS analysis we show that the compound 5a induces S/G2 cell cycle arrest, which was further supported by the observed down regulation of CDK2, Cyclin B1 and PCNA. The observed downregulation of proapoptotic proteins, upregulation of antiapoptotic proteins, cleavage of PARP and elevated levels of DNA strand breaks indicated the activation of apoptosis by 5a. These results suggest that 5a could be a potent anti-leukemic agent.

Optimal popular matchings

In this paper we consider the problem of computing an “optimal” popular matching. We assume that our input instance View the MathML source admits a popular matching and here we are asked to return not any popular matching but an optimal popular matching, where the definition of optimality is given as a part of the problem statement; for instance, optimality could be fairness in which case we are required to return a fair popular matching. We show an O(n2+m) algorithm for this problem, assuming that the preference lists are strict, where m is the number of edges in G and n is the number of applicants.

Popular Mixed Matchings

We study the problem of matching applicants to jobs under one-sided preferences: that is, each applicant ranks a non-empty subset of jobs under an order of preference, possibly involving ties. A matching M is said to be rnore popular than T if the applicants that prefer M to T outnumber those that prefer T to M. A matching is said to be popular if there is no matching more popular than it. Equivalently, a matching M is popular if phi(M,T) >= phi(T, M) for all matchings T, where phi(X, Y) is the number of applicants that prefer X to Y. Previously studied solution concepts based oil the popularity criterion are either not guaranteed to exist for every instance (e.g., popular matchings) or are NP-hard to compute (e.g., least unpopular matchings). This paper addresses this issue by considering mixed matchings. A mixed matching is simply a probability distributions over matchings in the input graph. The function phi that compares two matchings generalizes in a natural manner to mixed matchings by taking expectation. A mixed matching P is popular if phi(P,Q) >= phi(Q,P) for all mixed matchings Q. We show that popular mixed matchings always exist. and we design polynomial time algorithms for finding them. Then we study their efficiency and give tight bounds on the price of anarchy and price of stability of the popular matching problem.

Synthesis and Cytotoxic Evaluation of Novel 2-(4-(2,2,2-Trifluoroethoxy)-3-methylpyridin-2-ylthio)-1H-benzo[d]imid azole Derivatives

The present work deals with the anticancer effect of benzimidazole derivatives associated with the pyridine framework. By varying the functional group at N-terminal of the benzimidazole by different L-amino acids, several 2-(4-(2,2,2-trifluoroethoxy)-3-methylpyridin-2-ylthio)-1H-benzo[d]imid azole derivatives 9(a-j) were synthesized. Their chemical structures were confirmed by H-1 NMR, IR and mass spectroscopic techniques. The synthesized compounds were examined for their antiproliferative effects against human leukemia cell lines, K562 and CEM. The preliminary results showed most of the derivatives had moderate antitumor activity. Compound 9j containing cysteine residue exhibited good inhibition compared to other amino acid resides. In addition DNA fragmentation results suggest that 9j is more cytotoxic and able to induce apoptosis.

Limiting the Extent of the RDN1 Heterochromatin Domain by a Silencing Barrier and Sir2 Protein Levels in Saccharomyces cerevisiae

In Saccharomyces cerevisiae, transcriptional silencing occurs at the cryptic mating-type loci (HML and HMR), telomeres, and ribosomal DNA ( rDNA; RDN1). Silencing in the rDNA is unusual in that polymerase II (Pol II) promoters within RDN1 are repressed by Sir2 but not Sir3 or Sir4. rDNA silencing unidirectionally spreads leftward, but the mechanism of limiting its spreading is unclear. We searched for silencing barriers flanking the left end of RDN1 by using an established assay for detecting barriers to HMR silencing. Unexpectedly, the unique sequence immediately adjacent to RDN1, which overlaps a prominent cohesin binding site (CARL2), did not have appreciable barrier activity. Instead, a fragment located 2.4 kb to the left, containing a tRNA(Gln) gene and the Ty1 long terminal repeat, had robust barrier activity. The barrier activity was dependent on Pol III transcription of tRNA(Gln), the cohesin protein Smc1, and the SAS1 and Gcn5 histone acetyltransferases. The location of the barrier correlates with the detectable limit of rDNA silencing when SIR2 is overexpressed, where it blocks the spreading of rDNA heterochromatin. We propose a model in which normal Sir2 activity results in termination of silencing near the physical rDNA boundary, while tRNA(Gln) blocks silencing from spreading too far when nucleolar Sir2 pools become elevated.

Energy efficient change detection over a MAC using physical layer fusion

We propose a simple and energy efficient distributed change detection scheme for sensor networks based on Page's parametric CUSUM algorithm. The sensor observations are IID over time and across the sensors conditioned on the change variable. Each sensor runs CUSUM and transmits only when the CUSUM is above some threshold. The transmissions from the sensors are fused at the physical layer. The channel is modeled as a multiple access channel (MAC) corrupted with IID noise. The fusion center which is the global decision maker, performs another CUSUM to detect the change. We provide the analysis and simulation results for our scheme and compare the performance with an existing scheme which ensures energy efficiency via optimal power selection.

Linear time algorithms for Abelian group isomorphism and related problems

We consider the problem of determining if two finite groups are isomorphic. The groups are assumed to be represented by their multiplication tables. We present an O(n) algorithm that determines if two Abelian groups with n elements each are isomorphic. This improves upon the previous upper bound of O(n log n) [Narayan Vikas, An O(n) algorithm for Abelian p-group isomorphism and an O(n log n) algorithm for Abelian group isomorphism, J. Comput. System Sci. 53 (1996) 1-9] known for this problem. We solve a more general problem of computing the orders of all the elements of any group (not necessarily Abelian) of size n in O(n) time. Our algorithm for isomorphism testing of Abelian groups follows from this result. We use the property that our order finding algorithm works for any group to design a simple O(n) algorithm for testing whether a group of size n, described by its multiplication table, is nilpotent. We also give an O(n) algorithm for determining if a group of size n, described by its multiplication table, is Abelian. (C) 2007 Elsevier Inc. All rights reserved.

On a Special Co-cycle Basis of Graphs

In this paper we consider the problems of computing a minimum co-cycle basis and a minimum weakly fundamental co-cycle basis of a directed graph G. A co-cycle in G corresponds to a vertex partition (S,V ∖ S) and a { − 1,0,1} edge incidence vector is associated with each co-cycle. The vector space over ℚ generated by these vectors is the co-cycle space of G. Alternately, the co-cycle space is the orthogonal complement of the cycle space of G. The minimum co-cycle basis problem asks for a set of co-cycles that span the co-cycle space of G and whose sum of weights is minimum. Weakly fundamental co-cycle bases are a special class of co-cycle bases, these form a natural superclass of strictly fundamental co-cycle bases and it is known that computing a minimum weight strictly fundamental co-cycle basis is NP-hard. We show that the co-cycle basis corresponding to the cuts of a Gomory-Hu tree of the underlying undirected graph of G is a minimum co-cycle basis of G and it is also weakly fundamental.

New approximation algorithms for minimum cycle bases of graphs

We consider the problem of computing an approximate minimum cycle basis of an undirected edge-weighted graph G with m edges and n vertices; the extension to directed graphs is also discussed. In this problem, a {0,1} incidence vector is associated with each cycle and the vector space over F-2 generated by these vectors is the cycle space of G. A set of cycles is called a cycle basis of G if it forms a basis for its cycle space. A cycle basis where the sum of the weights of the cycles is minimum is called a minimum cycle basis of G. Cycle bases of low weight are useful in a number of contexts, e.g. the analysis of electrical networks, structural engineering, chemistry, and surface reconstruction. We present two new algorithms to compute an approximate minimum cycle basis. For any integer k >= 1, we give (2k - 1)-approximation algorithms with expected running time 0(kmn(1+2/k) + mn((1+1/k)(omega-1))) and deterministic running time 0(n(3+2/k)), respectively. Here omega is the best exponent of matrix multiplication. It is presently known that omega < 2.376. Both algorithms are o(m(omega)) for dense graphs. This is the first time that any algorithm which computes sparse cycle bases with a guarantee drops below the Theta(m(omega)) bound. We also present a 2-approximation algorithm with O(m(omega) root n log n) expected running time, a linear time 2-approximation algorithm for planar graphs and an O(n(3)) time 2.42-approximation algorithm for the complete Euclidean graph in the plane.

Replication of Japanese encephalitis virus in mouse brain induces alterations in lymphocyte response

The experimental model using intracerebral (i.c.) challenge was employed in many studies evaluating the protection against disease induced by Japanese encephalitis virus (JEV). We investigated alterations in peripheral lymphocyte response caused by i.c. infection of mice with JEV. Splenocytes from the i.c.-infected mice showed suppressed proliferative response to concanavalin A (con A) and anti-CD3 antibody stimulation. At the same time, the expression of CD25 (IL-2R) and production of IL-2 was inhibited. Addition of anti-CD28 antibody restored the decreased anti-CD3 antibody-mediated proliferation in the splenocytes. Moreover, the number of con A-stimulated cells secreting IL-4 was significantly reduced in splenocytes from i.c.-infected mice. These studies suggested that the i.c. infection with JEV might involve additional immune modulation effects due to massive virus replication in the brain.