Synthesis and identification of a new class of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzo[d]thiazole derivatives as potent antileukemic agents

Benzothiazoles are multitarget agents with broad spectrum of biological activity. Among the antitumor agents discovered in recent years, the identification of various 2-(4-aminophenyl) benzothiazoles as potent and selective antitumor drugs against different cancer cell lines has stimulated remarkable interest. Some of the benzothiazoles are known to induce cell cycle arrest, activation of caspases and interaction with DNA molecule. Based on these interesting properties of benzothiazoles and to obtain new biologically active agents, a series of novel 4,5,6,7-tetrahydrobenzo[d]thiazole derivatives 5(a-i) were synthesized and evaluated for their efficacy as antileukemic agents in human leukemia cells (K562 and Reh). The chemical structures of the synthesized compounds were confirmed by H-1 NMR, LCMS and IR analysis. The cytotoxicity of these compounds were determined using trypan blue exclusion, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Results showed that, these compounds mediate a significant cytotoxic response to cancer cell lines tested. We found that the compounds having electron withdrawing groups at different positions of the phenyl ring of the thiourea moiety displayed significant cytotoxic effect with IC50 value less than 60 mu M. To rationalize the role of electron withdrawing group in the induction of cytotoxicity, we have chosen molecule 5g (IC50 similar to 15 mu M) which is having chloro substitution at ortho and para positions. Flow cytometric analysis of annexin V-FITC/ propidium iodide (PI) double staining and DNA fragmentation suggest that 5g can induce apoptosis.

Voting Paths

We consider a variant of the popular matching problem here. The input instance is a bipartite graph $G=(\mathcal{A}\cup\mathcal{P},E)$, where vertices in $\mathcal{A}$ are called applicants and vertices in $\mathcal{P}$ are called posts. Each applicant ranks a subset of posts in an order of preference, possibly involving ties. A matching $M$ is popular if there is no other matching $M'$ such that the number of applicants who prefer their partners in $M'$ to $M$ exceeds the number of applicants who prefer their partners in $M$ to $M'$. However, the “more popular than” relation is not transitive; hence this relation is not a partial order, and thus there need not be a maximal element here. Indeed, there are simple instances that do not admit popular matchings. The questions of whether an input instance $G$ admits a popular matching and how to compute one if it exists were studied earlier by Abraham et al. Here we study reachability questions among matchings in $G$, assuming that $G=(\mathcal{A}\cup\mathcal{P},E)$ admits a popular matching. A matching $M_k$ is reachable from $M_0$ if there is a sequence of matchings $\langle M_0,M_1,\dots,M_k\rangle$ such that each matching is more popular than its predecessor. Such a sequence is called a length-$k$ voting path from $M_0$ to $M_k$. We show an interesting property of reachability among matchings in $G$: there is always a voting path of length at most 2 from any matching to some popular matching. Given a bipartite graph $G=(\mathcal{A}\cup\mathcal{P},E)$ with $n$ vertices and $m$ edges and any matching $M_0$ in $G$, we give an $O(m\sqrt{n})$ algorithm to compute a shortest-length voting path from $M_0$ to a popular matching; when preference lists are strictly ordered, we have an $O(m+n)$ algorithm. This problem has applications in dynamic matching markets, where applicants and posts can enter and leave the market, and applicants can also change their preferences arbitrarily. After any change, the current matching may no longer be popular, in which case we are required to update it. However, our model demands that we switch from one matching to another only if there is consensus among the applicants to agree to the switch. Hence we need to update via a voting path that ends in a popular matching. Thus our algorithm has applications here.

Deposition of ZnO Films by Combustion Flame Pyrolysis of Solution Precursors

The structural features,including preferred orientation and surface morphology of zinc oxide (ZnO) films deposited by combustion flame pyrolysis were investigated as a function of process parameters, which include precursor solution concentration, substrate-nozzle (S-N) distance, gas flow rate, and duration of deposition. In this technique, the precursor droplets react within the flame and form a coating on an amorphous silica substrate held in or near the flame. Depending on the process parameters, the state of decomposition at which the precursor arrives on the substrate varies substantially and this in turn dictates the orientation and microstructure of the films.

Synthesis and Antileukemic Activity of 1-((S)-2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-3-(substituted phenyl)urea Derivatives

Heterocyclic urea derivatives play an important role as anticancer agents because of their good inhibitory activity against receptor tyrosine kinases (RTKs), raf kinases, protein tyrosine kinases (PTKs), and NADH oxidase, which play critical roles in many aspects of tumorigenesis. Benzothiazole moiety constitutes an important scaffold of drugs, possessing several pharmacological functions, mainly the anticancer activity. Based on these interesting properties of benzothiazoles and urea moiety to obtain new biologically active agents, we synthesized a series of novel 1-((S)-2-amino-4,5,6.7-tetrahydrobenzo[d]thiazol-6-yl)-3-(substituted phenyl)urea derivatives and evaluated for their efficacy as antileukemic agents against two human leukemic cell lines (K562 and Reh). These compounds showed good and moderate cytotoxic effect to cancer cell lines tested. Compounds with electron-withdrawing chloro and fluoro substituents on phenyl ring showed good activity and compounds with electron-donating methoxy group showed moderate activity. Compound with electron-withdrawing dichloro substitution on phenyl ring of aryl urea showed good activity. Further, lactate dehydrogenase (LDH) assay, flow cytometric analysis of annexin V-FITC/propidium iodide (PI) double staining and DNA fragmentation studies showed that compound with dichloro substitution on phenyl ring of aryl urea can induce apoptosis.

Max-Coloring Paths: Tight Bounds and Extensions

The max-coloring problem is to compute a legal coloring of the vertices of a graph G = (V, E) with a non-negative weight function w on V such that Sigma(k)(i=1) max(v epsilon Ci) w(v(i)) is minimized, where C-1, ... , C-k are the various color classes. Max-coloring general graphs is as hard as the classical vertex coloring problem, a special case where vertices have unit weight. In fact, in some cases it can even be harder: for example, no polynomial time algorithm is known for max-coloring trees. In this paper we consider the problem of max-coloring paths and its generalization, max-coloring abroad class of trees and show it can be solved in time O(vertical bar V vertical bar+time for sorting the vertex weights). When vertex weights belong to R, we show a matching lower bound of Omega(vertical bar V vertical bar log vertical bar V vertical bar) in the algebraic computation tree model.

Popular Matchings with Variable Job Capacities

We consider the problem of matching people to jobs, where each person ranks a subset of jobs in an order of preference, possibly involving ties. There are several notions of optimality about how to best match each person to a job; in particular, popularity is a natural and appealing notion of optimality. However, popular matchings do not always provide an answer to the problem of determining an optimal matching since there are simple instances that do not adroit popular matchings. This motivates the following extension of the popular rnatchings problem:Given a graph G; = (A boolean OR J, E) where A is the set of people and J is the set of jobs, and a list < c(1), c(vertical bar J vertical bar)) denoting upper bounds on the capacities of each job, does there exist (x(1), ... , x(vertical bar J vertical bar)) such that setting the capacity of i-th, job to x(i) where 1 <= x(i) <= c(i), for each i, enables the resulting graph to admit a popular matching. In this paper we show that the above problem is NP-hard. We show that the problem is NP-hard even when each c is 1 or 2.

Faster Algorithms for All-pairs Approximate Shortest Paths in Undirected Graphs

Let G - (V, E) be a weighted undirected graph having nonnegative edge weights. An estimate (delta) over cap (u, v) of the actual distance d( u, v) between u, v is an element of V is said to be of stretch t if and only if delta(u, v) <= (delta) over cap (u, v) <= t . delta(u, v). Computing all-pairs small stretch distances efficiently ( both in terms of time and space) is a well-studied problem in graph algorithms. We present a simple, novel, and generic scheme for all-pairs approximate shortest paths. Using this scheme and some new ideas and tools, we design faster algorithms for all-pairs t-stretch distances for a whole range of stretch t, and we also answer an open question posed by Thorup and Zwick in their seminal paper [J. ACM, 52 (2005), pp. 1-24].

Differential regulation of MRN (Mre11-Rad50-Nbs1) complex subunits and telomerase activity in cancer cells

Several lines of evidence suggest that cancer progression is associated with up-regulation or reactivation of telomerase and the underlying mechanism remains an active area of research. The heterotrimeric MRN complex, consisting of Mre11, Rad50 and Nbs1, which is required for the repair of double-strand breaks, plays a key role in telomere length maintenance. In this study, we show significant differences in the levels of expression of MRN complex subunits among various cancer cells and somatic cells. Notably, siRNA-mediated depletion of any of the subunits of MRN complex led to complete ablation of other subunits of the complex. Treatment of leukemia and prostate cancer cells with etoposide lead to increased expression of MRN complex subunits, with concomitant decrease in the levels of telomerase activity, compared to breast cancer cells. These studies raise the possibility of developing anti-cancer drugs targeting MRN complex subunits to sensitize a subset of cancer cells to radio- and/or chemotherapy. (C) 2010 Elsevier Inc. All rights reserved.

Synthesis and Identification of a new class of antileukemic agents containing 2-(arylcarboxamide)-(S)-6-amino-4,5,6,7-tetrahydrobenzod]thiazole

Recently we have reported the effect of (S)-6-aryl urea/thiourea substituted-2-amino-4,5,6,7-tetrahydrobenzod]thiazole derivatives as potent anti-leukemic agents. To elucidate further the Structure Activity Relationship (SAR) studies on the anti-leukemic activity of (S)-2,6-diamino-4,5,6,7 tetrahydrobenzod]thiazole moiety, a series of 2-arlycarboxamide substituted-(S)-6-amino-4,5,6,7-tetrahydrobenzod]thiazole were designed, synthesized and evaluated for their anti-leukemic activity by trypan blue exclusion, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH) assays and cell cycle analysis. Results suggest that the position, number and bulkiness of the substituent on the phenyl ring of aryl carboxamide moiety at 2nd position of 6-amino-4,5,6,7-tetrhydrobenzod]thiazole play a key role in inhibiting the proliferation of leukemia cells. Compounds with ortho substitution showed poor activity and with meta and para substitution showed good activity. (C) 2010 Elsevier Masson SAS. All rights reserved.

New Approximation Algorithms for Minimum Cycle Bases of Graphs

We consider the problem of computing an approximate minimum cycle basis of an undirected non-negative 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. Although in most such applications any cycle basis can be used, a low weight cycle basis often translates to better performance and/or numerical stability. Despite the fact that the problem can be solved exactly in polynomial time, we design approximation algorithms since the performance of the exact algorithms may be too expensive for some practical applications. 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 O(kmn(1+2/k) + mn((1+1/k)(omega-1))) and deterministic running time O(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 expected running time O(M-omega root n log n), 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.

Popular matchings with variable item copies

We consider the problem of matching people to items, where each person ranks a subset of items in an order of preference, possibly involving ties. There are several notions of optimality about how to best match a person to an item; in particular, popularity is a natural and appealing notion of optimality. A matching M* is popular if there is no matching M such that the number of people who prefer M to M* exceeds the number who prefer M* to M. However, popular matchings do not always provide an answer to the problem of determining an optimal matching since there are simple instances that do not admit popular matchings. This motivates the following extension of the popular matchings problem: Given a graph G = (A U 3, E) where A is the set of people and 2 is the set of items, and a list < c(1),...., c(vertical bar B vertical bar)> denoting upper bounds on the number of copies of each item, does there exist < x(1),...., x(vertical bar B vertical bar)> such that for each i, having x(i) copies of the i-th item, where 1 <= xi <= c(i), enables the resulting graph to admit a popular matching? In this paper we show that the above problem is NP-hard. We show that the problem is NP-hard even when each c(i) is 1 or 2. We show a polynomial time algorithm for a variant of the above problem where the total increase in copies is bounded by an integer k. (C) 2011 Elsevier B.V. All rights reserved.

Additive Spanners and (alpha, beta)-Spanners

An (alpha, beta)-spanner of an unweighted graph G is a subgraph H that distorts distances in G up to a multiplicative factor of a and an additive term beta. It is well known that any graph contains a (multiplicative) (2k - 1, 0)-spanner of size O(n(1+1/k)) and an (additive) (1, 2)-spanner of size O(n(3/2)). However no other additive spanners are known to exist. In this article we develop a couple of new techniques for constructing (alpha, beta)-spanners. Our first result is an additive (1, 6)-spanner of size O(n(4/3)). The construction algorithm can be understood as an economical agent that assigns costs and values to paths in the graph, purchasing affordable paths and ignoring expensive ones, which are intuitively well approximated by paths already purchased. We show that this path buying algorithm can be parameterized in different ways to yield other sparseness-distortion tradeoffs. Our second result addresses the problem of which (alpha, beta)-spanners can be computed efficiently, ideally in linear time. We show that, for any k, a (k, k - 1)-spanner with size O(kn(1+1/k)) can be found in linear time, and, further, that in a distributed network the algorithm terminates in a constant number of rounds. Previous spanner constructions with similar performance had roughly twice the multiplicative distortion.

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 more 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 on 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 distribution 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. (C) 2010 Elsevier B.V. All rights reserved.

The TCP4 transcription factor of Arabidopsis blocks cell division in yeast at G1 -> S transition

The TCP transcription factors control important aspects of plant development. Members of class I TCP proteins promote cell cycle by regulating genes directly involved in cell proliferation. In contrast, members of class II TCP proteins repress cell division. While it has been postulated that class II proteins induce differentiation signal, their exact role on cell cycle has not been studied. Here, we report that TCP4, a class II TCP protein from Arabidopsis that repress cell proliferation in developing leaves, inhibits cell division by blocking G1 -> S transition in budding yeast. Cells expressing TCP4 protein with increased transcriptional activity fail to progress beyond G1 phase. By analyzing global transcriptional status of these cells, we show that expression of a number of cell cycle genes is altered. The possible mechanism of G1 -> S arrest is discussed. (C) 2011 Elsevier Inc. All rights reserved.

Hyper-activation of the TCP4 transcription factor in Arabidopsis thaliana accelerates multiple aspects of plant maturation

Plant organs are initiated as primordial outgrowths, and require controlled cell division and differentiation to achieve their final size and shape. Superimposed on this is another developmental program that orchestrates the switch from vegetative to reproductive to senescence stages in the life cycle. These require sequential function of heterochronic regulators. Little is known regarding the coordination between organ and organismal growth in plants. The TCP gene family encodes transcription factors that control diverse developmental traits, and a subgroup of class II TCP genes regulate leaf morphogenesis. Absence of these genes results in large, crinkly leaves due to excess division, mainly at margins. It has been suggested that these class II TCPs modulate the spatio-temporal control of differentiation in a growing leaf, rather than regulating cell proliferation per se. However, the link between class II TCP action and cell growth has not been established. As loss-of-function mutants of individual TCP genes in Arabidopsis are not very informative due to gene redundancy, we generated a transgenic line that expressed a hyper-activated form of TCP4 in its endogenous expression domain. This resulted in premature onset of maturation and decreased cell proliferation, leading to much smaller leaves, with cup-shaped lamina in extreme cases. Further, the transgenic line initiated leaves faster than wild-type and underwent precocious reproductive maturation due to a shortened adult vegetative phase. Early senescence and severe fertility defects were also observed. Thus, hyper-activation of TCP4 revealed its role in determining the timing of crucial developmental events, both at the organ and organism level.