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Lead para Saframycins are a group of Antitumor Antibiotics belonging to the Tetrahydroisoquinoline family. Initially discovered by Arai et al. in 1977, more than xx species have been discovered over the years, Saframycins generally have have low solubility in water and n-hexane, moderate solubility in ether and high solubility in lower alcohols, chloroform and acetone. They show varying degrees of antimicrobial properties on gram positive bacteria, and are generally effective against L1210 leukaemia. They also display activities against a variety of diseases such as Ehrlich ascites carcinoma, P388 leukaemia and B16 Melanoma. The saframycin compounds are currently not clinically prescribed for chemotherapy or otherwise due to its high toxicity, but their derivatives show potential as anti-tumour agents and going through clinical trials.

Body History The Saframycin group of compounds were first synthesized by Arai et al in 1977 using Streptomyces lavendulae (a streptothricin-producing strain), with the initial discovery consisting of Saframycin A, Saframycin B, Saframycin C, Saframycin D and Saframycin E. Structures of aforementioned compounds were subsequently published; the structure of Saframycin A was elucidated with 13C NMR spectroscopy at 1979, Saframycin C with X-ray Crystallography and Saframycin B with 13C NMR spectroscopy later in 1979, and Saframycin D with 400MHz NMR spectroscopy in 1987. Due to Saframycin E’s unstable nature, its structure was proposed by Kubo et al in 1995.

In the process of optimising production of Saframycin A, a precursor was discovered and isolated in 1981. It was then synthesised by treating Saframycin A with mild acid, which led to hydrolysis and decyanisation, yielding Saframycin S. Its structure was determined through various methods, including spectroscopic tests and chemical reactions.

In 1982, Arai et al. discovered Saframycin AR1(AH2), AR2, AH1 and AR3(BH1) as derivatives of Saframycin A, achieved by processing with R. amidophilus IFM44. Their structures were also determined through various methods consisting of multiple spectroscopic tests and chemical reactions. AH1 and AH2 would then go on to form AH1Ac and AH2Ac through acetylation.

Another variant, Saframycin R, was reported by Arai et al. in 1982 while investigating minor components in the Streptomyces lavendulae No.314 culture. 4 structures were proposed by Arai et al. in 1982 based on its spectroscopic and chemical data, and was confirmed by Kubo et al. in 2000 by running heteronuclear correlation experiments (HMQC and HMBC) on its acylated compounds.

Variants Saframycin F, G and H were isolated in 1984, and their structures were determined through various spectroscopic methods in 1988.

In 1985, Arai et al. attempted to alter the side chains of Saframycin A, which resulted in the generation of the new Saframycins Yd-1, Yd-2 and Y3, which had 2-amino-n-butyric acid, glycine, and alanine residues respectively substituting the pyruvic acid normally located in the N-terminal side chain of Saframycin A. In subsequent publications, similar methods with different reagents yielded the new compounds Ad-1, Y2b-d and Y2b, and structures of all aforementioned compounds were elucidated with spectroscopic methods.

MX1 and MX2 were discovered by Kienast et al. in the culture broth of Myxococcus xanthus (strain Mx x48). The isolated compounds were named Mx1 and Mx2, and the structures were elucidated -needs edit--.

Saf A Saf A Structure/properties Mechanism of action of Saf A Derivatives

Saf B Saf B Structure/properties

Saf C Saf C Structure/properties Saf C Applications

Saf D Saf D Structure/properties

Saf E Saf E Structure/properties

Clinical uses Saframycin A is one of the most well researched compounds among the saframycin family. Although highly potent and promising, its high toxicity prohibits its use as a chemotherapeutic drug; yet similar compounds show high potential as anti-tumour drugs and other purposes, and are currently undergoing clinical development.

Zalypsis Zalypsis is a synthetic alkaloid which is structurally related to the saframycin family. The drug is currently undergoing late phase 1 drug trials with the target of solid tumours and shows an acceptable toxicity profile along with high potency.