This review covers the highlights of combinatorial biosynthesis applied on post-polyketide synthase modifying enzymes, such as oxygenases. ketoreductases, glycosyl- and methyltransferases, acyltransferases, halogenases, cyclases and aminotransferases Since this is the first review on this topic, it covers literature from 1985 to 2002, and 248 references are given.

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Feeding experiments with 13C and 180-labeled precursors revealed that the molecular framework of the polycyclic xanthone antibiotics, the lysolipins X (1) and I (2), is derived from the polyketide pathway (12 malonate units), the Ci pool (methionine), molecular oxygen, and the nitrogen pool.Surprisingly, an intact malonate moiety serves as the three-carbon starter unit of the polyketide backbone, and 9 of the 12 oxygen atoms of 1 originate from molecular oxygen, including both of the xanthone oxygen atoms. The orientation of the malonate unit incorporated intact into lysolipin is unique and opposite from those in tetracycline and cycloheximide, i.e., the activated carbon of malonyl CoA is bound to the nitrogen of the lysolipin isoquinoline ring and the COa-derived carbon serves as the starter of the polyketide chain. From the biogenetic origin of the oxygen atoms several unusual prearomatic deoxygenation steps early in the biosynthesis have to be postulated.The polycyclic xanthone antibiotics form a small but distinct family of more than 20 members of microbial natural products. Their biological activities range from antibacterial (mainly Gram-positive bacteria including anaerobes,1-2 but also Gram-negative bacteria3), to anticoccidial,4 antifungal10•6 (e.g. yeasts, dermatophytes), and cytotoxic activities30•6 (e.g. HeLa cells).The lysolipins are antibacterial, antifungal (only 2), as well as cytotoxic compounds.3 After the albofungins,la~°t he lysolipins were the second group of the xanthone family of antibiotics to be discovered. These lipophilic antibiotics act lytically against cell walls, i.e., as inhibitors of cell wall biosynthesis (antagonism against lipid-bound mureine precursors).3® Lysolipin X (1) is the natural end product formed by Streptomyces violaceoniger (Tü 96) and the immediate precursor of lysolipin I (2), its dehydration product (Figure 1). While the absolute configuration of 2 could be established by X-ray analysis and chemical derivatization, the configuration of C-ll and C-12 in 1 is uncertain, because the instability of the molecule toward weak acids or light does not allow any chemical modificaf

Cytotoxic activities of jadomycin B and five new jadomycin derivatives against four cancer cell lines (HepG2, IM-9, IM-9/Bcl-2 and H460) were evaluated. Jadomycin S was most potent against HepG2, IM-9 and IM-9/Bcl-2 while jadomycin F was most potent against H460. Their potencies correlated with the degrees of apoptosis induced. Structure-activity-relationship analyses clearly demonstrate that the side chains of the oxazolone ring derived from the incorporated amino acids make a significant impact on biological activity. Therefore, jadomycin offers an ideal scaffold to manipulate structure and could be exploited to make many novel bioactive compounds with altered activities.

The use of complementary and alternative medicines for breast cancer patients has been increasing every year. Traditional Indian systems of medicine, such as Siddha, have been reported to benefit patients in India through herbal interventions for cancer. One such herbal medicine is Semecarpus Lehyam (SL), and this study aims at providing a scientific basis for the anti-tumor property of SL with respect to breast cancer. SL was subjected to serial extraction with four organic solvents of increasing polarity (n-hexane, chloroform, ethyl acetate, n-butanol and water). The solvents from all fractions were removed, dried and dissolved in dimethyl sulfoxide for testing their anti-tumor activity against two breast cancer cell lines, MCF-7 [estrogen receptor (ER)-positive] and MDA 231 (ER-negative) using cell viability and apoptosis assays. The most potent SL fractions were also combined with radiation and doxorubicin to determine the radio- and chemo-sensitizing effects of SL on these breast cancer cell lines. In terms of cytotoxicity as well as induction of apoptosis, the n-hexane and chloroform fractions of SL were more significantly active against MDA 231 cells than MCF-7 cells. The n-butanol fraction of SL showed some activity against MCF-7 cells. When combined with radiation or doxorubicin, the n-hexane and chloroform fractions enhanced the radio-sensitivity (11.8-fold) and chemo-sensitivity (6.5-fold) of MDA 231 cells. This study demonstrated SL to be a potent anti-tumor agent against the ER-negative breast cancer cell line. The study is also the first step in the scientific validation of SL for use against breast cancer, particularly the ER-negative type.