Kigamicins, Novel Antitumor Antibiotics: II. Structure Determination

Abstract

Kigamicin A (1), B (2), C (3), D (4) and E (5) are novel antitumor antibiotics. Their structures were determined by spectroscopic analyses including various NMR measurements. Kigamicins have a unique aglycone of fused octacyclic ring system containing seven of sixmembered rings and one oxazolidine. The aglycone links a sugar chain composed of one to four deoxysugars. These sugars were found to be amicetose and oleandrose.Kigamicins have been isolated from a culture broth of Amicolatopsis sp. ML630-mF1 as a result of their selective killing activity against PANC-1 cells only under a nutrient starvation condition1). They have antimicrobial activity against Gram-positive bacteria including Methicillin resistant Staphylococcus aureus (MRSA) and in vitro antitumor activity1). Kigamicin D showed good in vivo therapeutic activity against PANC-1 cells implanted into nude mice by subcutaneous or oral administration2). We herein describe the structure determination of kgamicins. Results and DiscussionThe structural studies were carried out first for kigamicin D (4), the major component of the antibiotics. The structures of other components were subsequently determined by comparing their spectral data with those of 4. Structure Determination of Kigamicin D (4)The molecular formula of kigamicin D (4) was established as C48H59NO19 (MW953)

Kigamicin D, a novel anticancer agent based on a new anti‐austerity strategy targeting cancer cells' tolerance to nutrient starvation

“…1), as a pale yellow powder, soluble in CHCl 3 , EtOAc, MeOH, and DMSO, but hardly soluble in water. 13,14) . As shown in Fig.…”

“…The process of purification and the determination of the molecular structure were described in detail in other papers. 13,14) Flow cytometric analysis. For flow cytometric analysis, PANC-1 cells were exposed to 0.1 µg/ml kigamicin D for 6 h, then both floating and trypsinized adherent cells were collected, washed with PBS, and incubated with 2.5% annexin V in binding buffer for 10 min, then with 2.5% propidium iodide in binding buffer (Bender Medsystems, Austria).…”

Antitumor activity of pyrvinium pamoate, 6‐(dimethylamino)‐2‐[2‐(2,5‐dimethyl‐1‐phenyl‐1H‐pyrrol‐3‐yl)ethenyl]‐1‐methyl‐quinolinium pamoate salt, showing preferential cytotoxicity during glucose starvation

“…Interestingly, the bromodeoxyuridine labeling indexes of PP-treated tumors were sometimes the same as or higher than those of untreated tumors, indicating a dynamic balance between cell growth and death in the tumors with smaller tumor volume treated with PP (our unpublished data). We recently discovered a novel compound, kigamicin D, 23,24) that exhibits selective toxicity during nutrient starvation and an antitumor effect that are similar to those of PP. Kigamicin D treatment causes a similar dynamic balance between cell growth and death in smaller tumors in vivo, and a similar effect on spheroid growth was also observed.…”

Synthesis and a Configurational Correlation within cis- and trans- Oxazolotetrahydroisoquinolinones with an Angular Substituent

“…The naturally occurring antibiotics cervinomycin A1 and A2 were synthesized in four to seven steps, where the last of these was the reaction of an isocoumarin with an imine [3 -5]. Kigamicins A, B, C, and D are novel anticancer agents containing one oxazolidine ring; they target the tolerance of cancer cells to nutrient starvation [6,7]. TMC-66 is a new endothelin-converting enzyme inhibitor, produced from the Streptomyces species A5008 [8].…”