The largely unexplored marine world that presumably harbors the most biodiversity may be the vastest resource to discover novel ‘validated’ structures with novel modes of action that cover biologically relevant chemical space. Several challenges, including the supply problem and target identification, need to be met for successful drug development of these often complex molecules; however, approaches are available to overcome the hurdles. Advances in technologies such as sampling strategies, nanoscale NMR for structure determination, total chemical synthesis, fermentation and biotechnology are all crucial to the success of marine natural products as drug leads. We illustrate the high degree of innovation in the field of marine natural products, which in our view will lead to a new wave of drugs that flow into the market and pharmacies in the future.

The identification of new pharmacophores is of paramount biomedical importance and natural products have recently been regaining attention for this endeavor. 1 This renaissance is closely tied to the successful exploitation of the marine environment which harbors unmatched biodiversity that is presumably concomitant with chemical diversity. 2 In particular, marine cyanobacteria are prolific producers of bioactive secondary metabolites, 3 many of which are modified peptides or peptide-polyketide hybrids with promising antitumor activities, such as dolastatin 10, 4 curacin A, 5 and apratoxin A. 6 As a result of our ongoing investigations to identify new drug leads from cyanobacteria in Florida, we report here the structure determination and preliminary biological characterization of a marine cyanobacterial metabolite with novel chemical scaffold and nanomolar antiproliferative activity from a cyanobacterium of the genus Symploca. Symploca species have scarcely been investigated compared to the more prevalent Lyngbya spp., yet a Palauan Symploca sp. previously yielded the clinical trial compound dolastatin 10, 4 prompting us to target this genus.A sample of Symploca sp. was collected from Key Largo, Florida Keys, and extracted with organic solvents. The resulting cytotoxic crude extract was subjected to bioassay-guided fractionation by solvent partition, silica gel chromatography, and reversed-phase HPLC to yield largazole (1) as a colorless, amorphous solid {[R] 20 D +22 (c 0.1, MeOH)}.

The potent antitumor agent dolastatin 10 (1) was originally isolated from the sea hare Dolabella auricularia, and we now report its isolation from the marine cyanobacterium Symploca sp. VP642 from Palau. The chemically related analogue symplostatin 1 (2) has been reisolated from Guamanian and Hawaiian varieties of S. hydnoides and its total stereochemistry completed by determining the N,N-dimethylisoleucine unit to be L. Symplostatin 1 (2), like dolastatin 10 (1), is a potent microtubule inhibitor. The antitumor activity of 2 was assessed in vivo against several murine tumors. Symplostatin 1 (2) was effective against a drug-insensitive mammary tumor and a drug-insensitive colon tumor; however, it was only slightly effective against two MDR tumors.