Identification and Preliminary Structure-Activity Relationship Studies of 1,5-Dihydrobenzo[e][1,4]oxazepin-2(3H)-ones That Induce Differentiation of Acute Myeloid Leukemia Cells In Vitro.

Acute myeloid leukemia (AML) is the most aggressive type of blood cancer, and there is a continued need for new treatments that are well tolerated and improve long-term survival rates in patients. Induction of differentiation has emerged as a promising alternative to conventional cytotoxic chemotherapy, but known agents lack efficacy in genetically distinct patient populations. Previously, we established a phenotypic screen to identify small molecules that could stimulate differentiation in a range of AML cell lines. Utilising this strategy, a 1,5-dihydrobenzo[e][1,4]oxazepin-2(3H)-one hit compound was identified. Herein, we report the hit validation in vitro, structure-activity relationship (SAR) studies and the pharmacokinetic profiles for selected compounds.

Spirocyclic Tetramates by Sequential Knoevenagel and [1,5]-Prototropic Shift.

Highly functionalized spirocyclic tetramates were prepared via a sequential Knoevenagel reaction and [1,5]-prototropic shift (T-reaction) of bicyclic tetramates. While these compounds isomerize in solution, stable analogues can be prepared via an appropriate choice of substituents. Further modification of these compounds allows for the introduction of aromatic groups, making them suitable as skeletons for application in medicinal chemistry.

Antibacterial Mimics of Natural Products by Side-Chain Functionalization of Bicyclic Tetramic Acids.

Tetramic acids with unsaturated acyl chains are widely found in natural products possessing a range of biological activities, and bicyclic tetramates represent a suitable scaffold to prepare simple mimics of such complex molecules. An efficient route to functionalize the C(6)-acyl group of a bicyclic tetramate was developed and utilized to prepare a small chemical library with a range of saturated and unsaturated side-chains. The analogues with lipophilic residues possessed highly potent antibacterial activity, which was selective for Gram-positive bacteria, and the best compound was 37-fold more potent than the cephalosporin C control and with an appropriate therapeutic window.

Diastereoselective reduction of the tricarbonyl moiety in bicyclic tetramates giving pyroglutamates.

The reduction of C(6)-acyl bicyclic tetramic acids has been achieved with complete diastereoselectivity via catalytic hydrogenation using PtO2. The resulting pyroglutamates had potent antibacterial and anticancer properties and will allow the preparation of simple mimics of pyroglutamate-containing natural products.

Aruncin B: Synthetic Studies, Structural Reassignment and Biological Evaluation.

A ring-closing alkene metathesis (RCM)/ oxyselenation-selenoxide elimination sequence was established to the sodium salts E- and Z-25 of the originally proposed structure for the recently isolated cytotoxin aruncin B (1), as well as to the sodium salt Z-34 of a related ethyl ether regioisomer; however, none of their corresponding free acids could be obtained. Their acid sensitivity, together with detailed analysis of the spectroscopic data indicated that profound structural revision was necessary. This led to reassignment of aruncin B as a Z-γ-alkylidenebutenolide Z-36. Although a related RCM/ oxyselenation-selenoxide elimination sequence was used to confirm the γ-alkylidenebutenolide motif, a ß-iodo Morita-Baylis-Hillman reaction/ Sonogashira cross-coupling-5-exo-dig lactonisation sequence was subsequently developed, due to its brevity and flexibility for diversification. Aruncin B (36), together with 14 γ-alkylidenebutenolide analogues, were generated for biological evaluation.

Synthesis and bioactivity of fused- and spiro-ß-lactone-lactam systems.

An investigation of the formation of fused- and spiro-ß-lactone annulate to γ-lactams has shown that the fused systems are formed preferentially, under standard conditions, but that spiro systems are accessible only when the formation of the fused system is blocked and require careful optimisation of reaction conditions. These systems display both weak antibacterial activity and proteasome inhibition.

Scalar Cross-Relaxation Detected in the NOESY Spectra of Oxazolidines and Thiazolidines.

Anomalous cross-peaks observed in the NOESY spectra of 2,4-disubstituted thiazolidines and oxazolidines that cannot be attributed to classical dipolar NOE or chemical exchange peaks have been investigated experimentally and computationally and have been shown to arise from scalar cross-relaxation of the first kind. This process is stimulated by the relatively slow modulation of scalar couplings and, for the systems studied, arises from slow on-off proton exchange of the amino nitrogen, a process influenced by solution temperature, acidity, and concentration. The mechanism is likely to be significant for many systems in which proton exchange occurs on the millisecond time scale, and misinterpretation of these cross-peaks may lead to erroneous conclusions should their true origins not be recognized.

Boosting the Impact of EFMC Young Scientists Network Through the Creation of Working Groups.

The establishment of the Young Scientists Network (YSN) by the European Federation for Medicinal Chemistry (EFMC) served as a proactive response to the evolving landscape of the scientific community. The YSN aims to assist early-career medicinal chemists and chemical biologists by responding to emerging themes, such as the influence of social media, shifts in gender balance within the scientific population, and evolving educational opportunities. The YSN also ensures that the upcoming generation of scientists actively contributes to shape the EFMC's strategic direction while addressing their specific needs. Initially conceived as a general concept, YSN has evolved into a proactive and dynamic team which demonstrates a tangible impact. To boost the impact of the YSN and involve additional motivated young scientists, we have adopted a novel organization, and structured the team in seven working groups (WGs). Herein, we will discuss the tasks of the different WGs as well as the activities planned for the near future. We believe this structure will strengthen the pivotal role YSN has already played in serving medicinal chemists and chemical biologists in Europe. The YSN now has the structure and motivation to pave the way to attract young scientists across Europe and to give them the stage within EFMC.

Visible-Light-Controlled Histone Deacetylase Inhibitors for Targeted Cancer Therapy.

The lack of selectivity of anticancer drugs limits current chemotherapy. Light-activatable drugs, whose activity can be precisely controlled with external light, could provide a more localized action of the drugs in the tumor, thus decreasing side effects and increasing efficacy. Herein, we introduce a series of photoswitchable azobenzene histone deacetylase inhibitors (HDACis) whose activity can be controlled by external visible light. Initial HDACis isomerized under ultraviolet light and were up to >50-fold more active under illumination than in the dark in enzyme assays. These were then optimized toward compounds responding to more permeable and less harmful green light by introducing o-halogen atoms into the azobenzene. Selected compounds decreased cell viability only under illumination in four different cancer cell lines. Overall, we present photoswitchable HDACis with optimized activation wavelengths, which inhibit enzyme activity and cell viability only upon illumination with visible light, contributing to the still limited toolbox of photoswitchable anticancer drugs.

Phenotypic screening identifies a trisubstituted imidazo[1,2-a]pyridine series that induces differentiation in multiple AML cell lines.

Acute myeloid leukaemia (AML) is an aggressive type of leukaemia with low rates of long-term survival. While the current standard of care is based on cytotoxic chemotherapy, a promising emerging approach is differentiation therapy. However, most current differentiating agents target specific mutations and are effective only in certain patient subtypes. To identify agents which may be effective in wider population cohorts, we performed a phenotypic screen with the myeloid marker CD11b and identified a compound series that was able to differentiate AML cell lines in vitro regardless of their mutation status. Structure-activity relationship studies revealed that replacing the formamide and catechol methyl ether groups with sulfonamide and indazole respectively improved the in vitro metabolic profile of the series while maintaining the differentiation profile in multiple cell lines. This optimisation exercise enabled progression of a lead compound to in vivo efficacy testing. Our work supports the promise of phenotypic screening to identify novel small molecules that induce differentiation in a wide range of AML subtypes.

A tubulin binding molecule drives differentiation of acute myeloid leukemia cells.

Despite much progress in developing better drugs, many patients with acute myeloid leukemia (AML) still die within a year of diagnosis. This is partly because it is difficult to identify therapeutic targets that are effective across multiple AML subtypes. One common factor across AML subtypes is the presence of a block in differentiation. Overcoming this block should allow for the identification of therapies that are not dependent on a specific mutation for their efficacy. Here, we used a phenotypic screen to identify compounds that stimulate differentiation in genetically diverse AML cell lines. Lead compounds were shown to decrease tumor burden and to increase survival in vivo. Using multiple complementary target deconvolution approaches, these compounds were revealed to be anti-mitotic tubulin disruptors that cause differentiation by inducing a G2-M mitotic arrest. Together, these results reveal a function for tubulin disruptors in causing differentiation of AML cells.

A Phenotypic Screen Identifies a Compound Series That Induces Differentiation of Acute Myeloid Leukemia Cells In Vitro and Shows Antitumor Effects In Vivo.

Induction of differentiation is a promising therapeutic strategy against acute myeloid leukemia. However, current differentiation therapies are effective only to specific patient populations. To identify novel differentiation agents with wider efficacy, we developed a phenotypic high-throughput screen with a range of genetically diverse cell lines. From the resulting hits, one chemical scaffold was optimized in terms of activity and physicochemical properties to yield OXS007417, a proof-of-concept tool compound, which was also able to decrease tumor volume in a murine in vivo xenograft model.

Asymmetric Total Synthesis of (-)-(3 R)-Inthomycin C.

A short (10 step) and efficient (15% overall yield) synthesis of the natural product (-)-(3 R)-inthomycin C is reported. The key steps comprise three C-C bond-forming reactions: (i) a vinylogous Mukaiyama aldol, (ii) an olefin cross-metathesis reaction, and (iii) an asymmetric Mukaiyama-Kiyooka aldol. This route is notable for its brevity and has the advantage of lacking stoichiometric tin-promoted cross-coupling reactions present in previous approaches. Initial investigations on the biological activity of (-)-(3 R)-inthomycin C and structural analogues on human cancer cell lines are also described for the first time.