The practical synthesis of a novel and highly potent analogue of bryostatin

Macrocycle 1 is a new highly potent analogue of bryostatin 1, a promising anti-cancer agent currently in human clinical trials. In vitro, 1 displays picomolar affinity for PKC and exhibits over 100-fold greater potency than bryostatin 1 when tested against various human cancer cell lines. Macrocycle 1 can be generated in clinically required amounts by chemical synthesis in only 19 steps (LLS) and represents a new clinical lead for the treatment of cancer.     

Role of the A-ring of bryostatin analogues in PKC binding: synthesis and initial biological evaluation of new A-ring-modified bryologs

The syntheses of three newly designed bryostatin analogues are reported. These simplified analogues, which lack the A-ring present in the natural product but possess differing groups at C9, were obtained using a divergent approach from a common intermediate. All three analogues exhibit potent, single-digit nanomolar affinity to protein kinase C.     

Overlap Cycles for Steiner Quadruple Systems

Steiner quadruple systems are set systems in which every triple is contained in a unique quadruple. It is well known that Steiner quadruple systems of order v, or SQS(v), exist if and only if . Universal cycles, introduced by Chung, Diaconis, and Graham in 1992, are a type of cyclic Gray code. Overlap cycles are generalizations of universal cycles that were introduced in 2010 by Godbole, et al. Using Hanani's SQS constructions, we show that for every with there exists an SQS(v) that admits a 1‐overlap cycle.     

1-Overlap cycles for Steiner triple systems

A number of applications of Steiner triple systems (e.g. disk erasure codes) exist that require a special ordering of its blocks. Universal cycles, introduced by Chung, Diaconis, and Graham in 1992, and Gray codes are examples of listing elements of a combinatorial family in a specific manner, and Godbole invented the following generalization of these in 2010. 1-overlap cycles require a set of strings to be ordered so that the last letter of one string is the first letter of the next. In this paper, we prove the existence of 1-overlap cycles for automorphism free Steiner triple systems of each possible order. Since Steiner triple systems have the property that each block can be represented uniquely by a pair of points, these 1-overlap cycles can be compressed by omitting non-overlap points to produce rank two universal cycles on such designs, expanding on the results of Dewar.     

DYNGA: a general purpose QM-MM-MD program. I. Application to water

We present a general purpose QM-MM-MD engine (DYNGA) designed to test alternative hybrid Hamiltonians geared towards the treatment of problems of interest in structural biology including the use of experimental data constraints. In this first presentation we use DYNGA to explore the behaviour of a traditional QM-MM approach in the treatment of the water—water interaction. We find the potential energy hypersurface for the water dimer computed with the HF 4–31G*/TIP3P hybrid Hamiltonian tends to be too flat. We also explore the effect of using traditional QM-MM techniques on proton wires and conclude there is a need for improvement, possibly addressed by using polarizable force fields.