Lavendamycin

A series of lavendamycin analogues with two, three or four substituents at the C-6, C-7 N, C-2', C-3' and C-11' positions were synthesized via short and efficient methods and evaluated as potential NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor agents. The compounds were prepared through Pictet-Spengler condensation of the desired 2-formylquinoline-5,8-diones with the required tryptophans followed by further needed transformations. Metabolism and toxicity studies demonstrated that the best substrates for NQO1 were also the most selectively toxic to NQO1-rich tumor cells compared to NQO1-deficient tumor cells.

The title compound, C(27)H(24)N(4)O(5), is an inter-mediate in the synthesis of lavendamycin via a ruthenium-catalysed [2 + 2 + 2] cyclo-addition. An intra-molecular hydrogen-bond bridge from the carboline to the quinoline stabilizes a highly planar geometry [maximum deviation = 0.065 (6) Å] for the two rigid units. This hydrogen-bond-stabilized coplanarity has a very close analogy in the structure of the anti-tumor anti-biotic streptonigrin in the solid state and in solution. Inter-molecular hydrogen-bond bridges of amides groups along the a axis and π-π stacking inter-actions [centroid-centroid distance = 3.665 (9) Å] connect mol-ecules arranged in a parallel manner.

Lavendamycin methyl ester (LME) is a derivative of a highly functionalized aminoquinone alkaloid lavendamycin and could be used as a scaffold for novel anticancer agent development. This work demonstrated LME production by cultivation of an engineered strain of Streptomyces flocculus CGMCC4.1223 ΔstnB1, while the wild-type strain did not produce. To enhance its production, the effect of shear stress and oxygen supply on ΔstnB1 strain cultivation was investigated in detail. In flask culture, when the shaking speed increased from 150 to 220 rpm, the mycelium was altered from a large pellet to a filamentous hypha, and the LME production was almost doubled, while no significant differences were observed among varied filling volumes, which implied a crucial role of shear stress in the morphology and LME production. To confirm this suggestion, experiments with agitation speed ranging from 400 to 1,000 rpm at a fixed aeration rate of 1.0 vvm were conducted in a stirred tank bioreactor. It was found that the morphology became more hairy with reduced pellet size, and the LME production was enhanced threefolds when the agitation speed increased from 400 to 800 rpm. Further experiments by varying initial k L a value at the same agitation speed indicated that oxygen supply only slightly affected the physiological status of ΔstnB1 strain. Altogether, shear stress was identified as a major factor affecting the cell morphology and LME production. The work would be helpful to the production of LME and other secondary metabolites by filamentous microorganism cultivation.