Challenges in the structure determination of a dimeric impurity found during development of GDC-0326.

While developing a synthetic route for GDC-0326, a PI3Kα selective inhibitor, a side product was identified which was adversely impacting process chemistry development. To aid in optimization of a viable synthetic pathway for the drug, it was decided to characterize this impurity. Initial efforts using typical high-resolution mass spectrometry data coupled with NMR analysis were unable to unambiguously identify the structure.

Highly Efficient Synthesis of a Staphylococcus aureus Targeting Payload to Enable the First Antibody-Antibiotic Conjugate.

A practical synthesis of the complex payload for an anti-Staphylococcus aureus THIOMAB antibody-antibiotic conjugate (TAC) is described. The route takes advantage of a delicate oxidative condensation, achieved using a semi-continuous flow procedure. It allows for the generation of kilogram quantities of a key intermediate to enable a mild nucleophilic aromatic substitution to the tertiary amine free drug.

CYP1A1-Mediated Intramolecular Rearrangement of Aminoazepane in GDC-0339.

GDC-0339 is a novel small molecule pan-Pim kinase inhibitor that was discovered as a potential treatment of multiple myeloma. During the in vitro and in vivo metabolite profiling of GDC-0339, a metabolite was detected that had the same elemental composition as the parent but was distinct with respect to its chromatographic separation and mass spectrometric fragmentation pattern. High resolution tandem mass spectrometry data indicated the metabolite was modified at the aminoazepane moiety.

Targeted drug delivery through the traceless release of tertiary and heteroaryl amines from antibody-drug conjugates.

The reversible attachment of a small-molecule drug to a carrier for targeted delivery can improve pharmacokinetics and the therapeutic index. Previous studies have reported the delivery of molecules that contain primary and secondary amines via an amide or carbamate bond; however, the ability to employ tertiary-amine-containing bioactive molecules has been elusive. Here we describe a bioreversible linkage based on a quaternary ammonium that can be used to connect a broad array of tertiary and heteroaryl amines to a carrier protein.

Degradation of a pharmaceutical in HPLC grade methanol containing trace level formaldehyde.

An anomalous peak was observed in the HPLC/UV analysis of a developmental drug product. High resolution LC/MS revealed that the mass of this degradant was 12 Da greater than the drug substance, corresponding to a net gain of a single carbon atom. The degradant was reproduced by incubating the drug substance with formaldehyde, followed by isolation using normal phase chromatography and structure elucidation by NMR.

An isolable acyclic hemiacetal of ansamitocin P-3.

During impurity analysis of maytansinol (2), produced from the reduction of ansamitocin P-3 (AP-3, 1), a surprisingly stable acyclic hemiacetal (4) was isolated. A combination of 1D and 2D NMR experiments, along with liquid chromatography-mass spectrometry data was used to confirm the structure. Comparison of NMR data to the previously reported bridged acetal (3), a by-product of AP-3 reduction, supports reassignment of the latter to the former.

Assessing pressurized liquid extraction for the high-throughput extraction of marine-sponge-derived natural products.

In order to compare the utility of standard solvent partitioning (SSP) versus accelerated solvent extraction (ASE), a series of experiments were performed and evaluated. Overall yields, solvent consumption, processing time, and chemical stability of the fractions obtained by both methods were compared. Five marine sponges were selected for processing and analysis containing 12 structurally distinct, bioactive natural products.

Investigation of brominated tryptophan alkaloids from two thorectidae sponges: Thorectandra and Smenospongia.

Chemical investigation of an NCI-DTP collection of Thorectandra sp. and a UCSC collection of Smenospongia sp. yielded six new brominated tryptophan derivatives: 6-bromo-1'-hydroxy-1',8-dihydroaplysinopsin (4), 6-bromo-1'-methoxy-1',8-dihydroaplysinopsin (5), 6-bromo-1'-ethoxy-1',8-dihydroaplysinopsin (6), (-)-5-bromo-N,N-dimethyltryptophan (7), (+)-5-bromohypaphorine (8), and 6-bromo-1H-indole-3-carboxylic acid methyl ester (11).

A Madagascar Sponge Batzella sp. as a source of alkylated iminosugars.

Three new C-alkylated iminosugars, batzellasides A (3), B (4), and C (5), along with the known halitoxin (2) polymer were isolated from a Batzella sp. sponge, collected off the west coast of Madagascar. Although this class of azasugars is well known from terrestrial sources, our report represents the first examples of iminosugars from a marine organism.

Probing the activity differences of simple and complex brominated aryl compounds against 15-soybean, 15-human, and 12-human lipoxygenase.

Lipoxygenases (LO) have been implicated in asthma, immune disorders, and various cancers. As a consequence of these broad biological implications, there is great interest in understanding the effects of naturally occurring and environmental contaminants against its activity. On the basis of our earlier studies indicating that polybrominated diphenol ethers are potent inhibitors to mammalian 15-LO, we expanded our structure-activity study to include marine-derived brominated phenol ethers (including a newly discovered tribrominated diphenyl ether), dioxins, and bastadins, as well as the synthetic brominated fire retardants, brominated bisphenol A (BBPA), and polybrominated diphenyl ethers (PBDEs).

Comparison of fascaplysin and related alkaloids: a study of structures, cytotoxicities, and sources.

The fascaplysin class of compounds have been further investigated from six organisms consisting of four sponge collections (Fascaplysinopsis reticulata) and two tunicate collections (Didemnum sp.). This work is an extension of an earlier communication and reports the isolation of 12 new fascaplysin derivatives: 10-bromofascaplysin (7), 3,10-dibromofascaplysin (8), homofascaplysate A (9), homofascaplysin B-1 (11), 3-bromohomofascaplysins B (12), B-1 (13), and C (15), 7,14-dibromoreticulatine (17), reticulatol (20), 14-bromoreticulatol (21), and 3-bromosecofascaplysins A (22) and B (23), along with known compounds: fascaplysin (1), reticulatine (4), 3-bromofascaplysin (6), and homofascaplysin C (14).